Methods for modulating rna splicing

ABSTRACT

In one aspect, described herein is a recognition element for splicing modifier (REMS) that can be recognized by a compound provided herein. In another aspect, described herein are methods for modulating the amount of a product of a gene, wherein a precursor RNA transcript transcribed from the gene contains a REMS, and the methods utilizing a compound described herein. More particularly, described herein are methods for modulating the amount of an RNA transcript or protein product encoded by a gene, wherein a precursor RNA transcript transcribed from the gene comprises a REMS, and the methods utilizing a compound described herein. In another aspect, provided herein are artificial gene constructs comprising a REMS, and uses of those artificial gene constructs to modulate functional protein production. In another aspect, provided herein are methods for altering endogenous genes to comprise a REMS, and the use of a compound described herein to modulate the functional protein produced from such altered endogenous genes.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application_is a divisional of U.S. patent application Ser. No.15/577,584 (now U.S. Pat. No. 10,668,171 B2), which is a U.S. NationalStage Application of International Patent Application No.PCT/US2016/034864, filed May 27, 2016, which claims the benefit of U.S.Provisional Application No. 62/168,726, filed on May 30, 2015, thecontent of each of which is incorporated by reference herein in itsentirety.

This application incorporates by reference in its entirety the ComputerReadable Form (“CRF”) of a Sequence Listing in ASCII text formatsubmitted via EFS-Web. The Sequence Listing text file submitted viaEFS-Web is entitled “10589-300-999_SEQ_LISTING.txt,” was created on Apr.5, 2020 and is 29,856 bytes in size.

INTRODUCTION

In one aspect, described herein is a recognition element for splicingmodifier (REMS) that can be recognized by a compound provided herein. Inanother aspect, described herein are methods for modulating the amountof a product of a gene, wherein a precursor RNA transcript transcribedfrom the gene contains a REMS, and the methods utilize a compounddescribed herein. More particularly, described herein are methods formodulating the amount of an RNA transcript or protein product encoded bya gene, wherein a precursor RNA transcript transcribed from the genecomprises a REMS, and the methods utilize a compound described herein.In another aspect, provided herein are artificial gene constructscomprising a REMS, and uses of those artificial gene constructs tomodulate functional protein production. In another aspect, providedherein are methods for altering endogenous genes to comprise a REMS, andthe use of a compound described herein to modulate the functionalprotein produced from such altered endogenous genes.

BACKGROUND

A number of diseases are associated with aberrant expression of a geneproduct (e.g., an RNA transcript or protein) of a gene. The resultingaberrant amounts of RNA transcripts may lead to disease due tocorresponding changes in protein expression. Changes in the amount of aparticular RNA transcript may be the result of several factors. First,changes in the amount of RNA transcripts may be due to an aberrant levelof transcription of a particular gene, such as by the perturbation of atranscription factor or a portion of the transcription process,resulting in a change in the expression level of a particular RNAtranscript. Second, changes in the splicing of particular RNAtranscripts, such as by perturbation of a particular splicing process ormutations in the gene that lead to modified splicing can change thelevels of a particular RNA transcript. Changes to the stability of aparticular RNA transcript or to components that maintain RNA transcriptstability, such as the process of poly-A tail incorporation or an effecton certain factors or proteins that bind to and stabilize RNAtranscripts, may lead to changes in the levels of a particular RNAtranscript. Also, the level of translation of particular RNA transcriptscan affect the amount of those transcripts, affecting or upregulatingRNA transcript decay processes. Finally, aberrant RNA transport or RNAsequestration may also lead to changes in functional levels of RNAtranscripts, and may have an effect on the stability, furtherprocessing, or translation of the RNA transcripts.

Often, diseases associated with changes to RNA transcript amount aretreated with a focus on the aberrant protein expression. However, if theprocesses responsible for the aberrant changes in RNA levels, such ascomponents of the splicing process or associated transcription factorsor associated stability factors, could be targeted by treatment with asmall molecule, it would be possible to restore protein expressionlevels such that the unwanted effects of the expression of aberrantlevels of RNA transcripts or associated proteins. Therefore, there is aneed for methods of modulating the amount of RNA transcripts encoded bycertain genes as a way to prevent or treat diseases associated withaberrant expression of the RNA transcripts or associated proteins.

SUMMARY

In one aspect, provided herein is a recognition element for splicingmodifier (otherwise referred to as “REMS”) that plays a role in therecognition of a compound described herein. In a specific embodiment,the REMS has the nucleotide sequence GAgurngn (SEQ ID NO: 1) at the RNAlevel, wherein r is A or G (i.e., a purine nucleotide) and n is anynucleotide. In another specific embodiment, the REMS has the nucleotidesequence GAguragu (SEQ ID NO: 2) at the RNA level, wherein r is A or G.In another specific embodiment, the REMS has the nucleotide sequenceANGAgurngn (SEQ ID NO: 3) at the RNA level, wherein r is A or G (i.e., apurine nucleotide) and n or N is any nucleotide. In a preferredembodiment, the REMS has the nucleotide sequence ANGAguragu (SEQ ID NO:4) at the RNA level, wherein r is A or G and N is any nucleotide. In aspecific embodiment, the REMS is located in the 5′ splice site. Incertain embodiments, the REMS is located within an exon, such as inFoxM1 exon 7a. Without being bound by any theory or mechanism, it isbelieved that compounds described herein increase the affinity of theinteraction between U1 snRNP and the nucleotides ANGA (SEQ ID NO: 9) ofthe REMS. This belief is based, in part, on the recognition that REMScomprises the U1 snRNP binding site.

In FIG. 1D, the REMS is located in the 5′ splice site of a precursor RNA(e.g., precursor mRNA). In the presence of a compound described herein,the nucleotides between the REMS in the 5′ splice site and a downstream3′ splice site of a precursor RNA (except the nucleotides of the exon)are removed and the exons of the precursor RNA are spliced together. InFIG. 1B, the REMS is located within an exon in a precursor RNA. In thepresence of a compound described herein, the nucleotides between theREMS and a downstream 3′ splice site of a precursor RNA (exceptnucleotides GA or ANGA of REMS) are removed and the remaining portionsof the precursor RNA are spliced together, which may result in an RNAtranscript with a truncated open reading frame due to a frameshift orinternal deletions within the open reading frame.

Accordingly, in one aspect, provided herein are methods for modulatingthe amount of RNA transcript produced from precursor RNA containing aREMS. In another aspect, provided herein are artificial gene constructscomprising a REMS, which may be used in the context of, e.g., genetherapy or reporter assays. In another aspect, provided herein aremethods for altering endogenous genes so that they contain a REMS or anadditional REMS.

In another aspect, provided herein are methods for modulating the amountof one or more RNA transcripts (e.g., mRNA transcripts) or proteinsthereof expressed as the product of one or more genes, wherein precursorRNA transcripts transcribed by the one or more genes comprise a REMS,the methods comprising contacting a cell with a compound of Formula (I)

or a form thereof, wherein w₁, w₂, w₃, w₄, w₅, w₆ and w₇ are as definedherein. In one embodiment, provided herein is a method for modulatingthe amount of an RNA transcript produced from precursor RNA containing arecognition element for splicing modifier (REMS), the method comprisingcontacting a cell containing the precursor RNA with a compound ofFormula (I) or a form thereof, wherein the REMS comprises the sequenceGAgurngn (SEQ ID NO: 1), wherein r is A or G and n is any nucleotide,wherein the precursor RNA is not a gene in Table 6. In anotherembodiment, provided herein is a method for modulating the amount of anRNA transcript produced from precursor RNA containing a recognitionelement for splicing modifier (REMS), the method comprising contactingthe precursor RNA with a compound of Formula (I) or a form thereof,wherein the REMS comprises the sequence GAgurngn (SEQ ID NO: 1), whereinr is A or G and n is any nucleotide, wherein the precursor RNA is not agene in Table 6. In some embodiments, the REMS comprises the sequenceGAguragu (SEQ ID NO: 2) at the RNA level, wherein r is A or G. Incertain embodiments, the REMS comprises the sequence ANGAgurngn (SEQ IDNO: 3), wherein r is A or G and n or N is any nucleotide. In someembodiments, the REMS comprises the sequence ANGAguragu (SEQ ID NO: 4)at the RNA level, wherein r is A or G, and N is any nucleotide.

In another embodiment, provided herein is a method for modulating theamount of an RNA transcript produced from precursor RNA encoded by thegene ERGIC3, the method comprising contacting a cell containing theprecursor RNA with a compound of Formula (I) or a form thereof. Inanother embodiment, provided herein is a method for modulating theamount of an RNA transcript produced from precursor RNA encoded by thegene ERGIC3, the method comprising contacting the precursor RNA with acompound of Formula (I) or a form thereof. In some embodiments, the REMScomprises the sequence GAguragu (SEQ ID NO: 2) at the RNA level, whereinr is A or G. In certain embodiments, the REMS comprises the sequenceANGAgurngn (SEQ ID NO: 3), wherein r is A or G and n or N is anynucleotide. In some embodiments, the REMS comprises the sequenceANGAguragu (SEQ ID NO: 4) at the RNA level, wherein r is A or G, and Nis any nucleotide.

In one embodiment, provided herein are methods for modulating the amountof one, two, three or more RNA transcripts of a gene, by way ofnonlimiting example, disclosed in Table 6, infra, the method comprisingcontacting a cell with a compound of Formula (I) or a form thereof. Inanother embodiment, provided herein are methods for modulating theamount of one, two, three or more RNA transcripts of a gene, notdisclosed in Tables 1-4, infra, wherein the precursor transcripttranscribed from the gene comprises a REMS, the method comprisingcontacting a cell with a compound of Formula (I) or a form thereof. Inanother embodiment, provided herein are methods for modulating theamount of one, two, three or more RNA transcripts of a gene, notdisclosed in International Patent Application No. PCT/US2014/071252(International Publication No. WO 2015/105657 A1), wherein the precursortranscript transcribed from the gene comprises a REMS, the methodcomprising contacting a cell with a compound of Formula (I) or a formthereof.

In another embodiment, provided herein are methods for modulating theamount of one, two, three or more RNA transcripts of a gene, notdisclosed in Table 6, infra, wherein the precursor transcripttranscribed from the gene comprises a REMS, the method comprisingcontacting a cell with a compound of Formula (I) or a form thereof. Inanother embodiment, provided herein are methods for modulating theamount of one, two, three or more RNA transcripts of ERGIC3, comprisingcontacting a cell with a compound of Formula (I) or a form thereof. Seethe example section for additional information regarding the genes inTable 6. In certain embodiments, the cell is contacted with the compoundof Formula (I) or a form thereof in a cell culture. In otherembodiments, the cell is contacted with the compound of Formula (I) or aform thereof in a subject (e.g., a non-human animal subject or a humansubject). In certain embodiments, a compound of Formula (I) is acompound of Formula (II), Formula (III), Formula (IV), Formula (V),Formula (VI), Formula (VII), Formula (VIII), Formula (IX), Formula (X),Formula (XI), Formula (XII), Formula (XIII), or Formula (XIV) describedinfra. In some embodiments, a compound of Formula (I) is a compoundselected from a compound described herein.

In another aspect, provided herein are methods for modulating the amountof one, two, three or more RNA transcripts of a gene, wherein theprecursor RNA transcript transcribed from the gene comprises a REMS, themethods comprising administering to a patient in need thereof a compoundof Formula (I) or a form thereof, or a pharmaceutical compositioncomprising a compound of Formula (I) or a form thereof and apharmaceutically acceptable carrier, excipient or diluent. In oneembodiment, provided herein are methods for modulating the amount ofone, two, three or more RNA transcripts of a gene, by way of nonlimitingexample, disclosed in Table 6, infra, the methods comprisingadministering to a patient in need thereof a compound of Formula (I) ora form thereof, or a pharmaceutical composition comprising a compound ofFormula (I) or a form thereof and a pharmaceutically acceptable carrier,excipient or diluent.

In another embodiment, provided herein are methods for modulating theamount of one, two, three or more RNA transcripts of a gene, notdisclosed in Tables 1-4, infra, wherein the precursor RNA transcripttranscribed from the gene comprises a REMS, the methods comprisingadministering to a patient in need thereof a compound of Formula (I) ora form thereof, or a pharmaceutical composition comprising a compound ofFormula (I) or a form thereof and a pharmaceutically acceptable carrier,excipient or diluent.

In another embodiment, provided herein are methods for modulating theamount of one, two, three or more RNA transcripts of a gene, notdisclosed in International Patent Application No. PCT/US2014/071252(International Publication No. WO 2015/105657 A1), wherein the precursorRNA transcript transcribed from the gene comprises a REMS, the methodscomprising administering to a patient in need thereof a compound ofFormula (I) or a form thereof, or a pharmaceutical compositioncomprising a compound of Formula (I) or a form thereof and apharmaceutically acceptable carrier, excipient or diluent. In anotherembodiment, provided herein are methods for modulating the amount ofone, two, three or more RNA transcripts of a gene, not disclosed inTable 6, infra, wherein the precursor RNA transcript transcribed fromthe gene comprises a REMS, the methods comprising administering to apatient in need thereof a compound of Formula (I) or a form thereof, ora pharmaceutical composition comprising a compound of Formula (I) or aform thereof and a pharmaceutically acceptable carrier, excipient ordiluent.

In another embodiment, provided herein are methods for modulating theamount of one, two, three or more RNA transcripts of ERGIC3, comprisingadministering to a patient in need thereof a compound of Formula (I) ora form thereof, or a pharmaceutical composition comprising a compound ofFormula (I) or a form thereof and a pharmaceutically acceptable carrier,excipient or diluent. See the example section for additional informationregarding the genes in Table 6. In certain embodiments, a compound ofFormula (I) is a compound of Formula (II), Formula (III), Formula (IV),Formula (V), Formula (VI), Formula (VII), Formula (VIII), Formula (IX),Formula (X), Formula (XI), Formula (XII), Formula (XIII), or Formula(XIV) described infra. In some embodiments, a compound of Formula (I) isa compound selected from a compound described herein.

In another aspect, provided herein are methods for preventing and/ortreating a disease associated with the aberrant expression of a productof a gene (e.g., an mRNA transcript or protein), wherein the precursorRNA transcript transcribed from the gene comprises a REMS, the methodscomprising administering to a patient in need thereof a compound ofFormula (I) or a form thereof, or a pharmaceutical compositioncomprising a compound of Formula (I) or a form thereof and apharmaceutically acceptable carrier, excipient or diluent. In oneembodiment, provided herein are methods for preventing and/or treating adisease associated with aberrant expression of a product of a gene(e.g., an mRNA, RNA transcript or protein), by way of nonlimitingexample, disclosed in Table 6, infra, the methods comprisingadministering to a patient in need thereof a compound of Formula (I) ora form thereof, or a pharmaceutical composition comprising a compound ofFormula (I) or a form thereof and a pharmaceutically acceptable carrier,excipient or diluent. In another embodiment, provided herein are methodsfor preventing and/or treating a disease associated with aberrantexpression of a product of a gene (e.g., an mRNA, RNA transcript orprotein), not disclosed in Tables 1-4, infra, wherein the precursor RNAtranscript transcribed from the gene comprises a REMS, the methodscomprising administering to a patient in need thereof a compound ofFormula (I) or a form thereof, or a pharmaceutical compositioncomprising a compound of Formula (I) or a form thereof and apharmaceutically acceptable carrier, excipient or diluent. In anotherembodiment, provided herein are methods for preventing and/or treating adisease associated with aberrant expression of a product of a gene(e.g., an mRNA, RNA transcript or protein), by way of nonlimitingexample, not disclosed in International Patent Application No.PCT/US2014/071252 (International Publication No. WO 2015/105657 A1),wherein the precursor RNA transcript transcribed from the gene comprisesa REMS, the methods comprising administering to a patient in needthereof a compound of Formula (I) or a form thereof, or a pharmaceuticalcomposition comprising a compound of Formula (I) or a form thereof and apharmaceutically acceptable carrier, excipient or diluent. In anotherembodiment, provided herein are methods for preventing and/or treating adisease associated with aberrant expression of a product of a gene(e.g., an mRNA, RNA transcript or protein), not disclosed in Table 6,infra, wherein the precursor RNA transcript transcribed from the genecomprises a REMS, the methods comprising administering to a patient inneed thereof a compound of Formula (I) or a form thereof, or apharmaceutical composition comprising a compound of Formula (I) or aform thereof and a pharmaceutically acceptable carrier, excipient ordiluent. In another embodiment, provided herein are methods forpreventing and/or treating a disease associated with aberrant expressionof a product of ERGIC3 (e.g., an mRNA, RNA transcript or protein),comprising administering to a patient in need thereof a compound ofFormula (I) or a form thereof, or a pharmaceutical compositioncomprising a compound of Formula (I) or a form thereof and apharmaceutically acceptable carrier, excipient or diluent. See theexample section for additional information regarding the genes in Table6. In certain embodiments, a compound of Formula (I) is a compound ofFormula (II), Formula (III), Formula (IV), Formula (V), Formula (VI),Formula (VII), Formula (VIII), Formula (IX), Formula (X), Formula (XI),Formula (XII), Formula (XIII), or Formula (XIV) described infra. In someembodiments, a compound of Formula (I) is a compound selected from acompound described herein.

In another aspect, provided herein are methods for preventing and/ortreating a disease in which a change in the level of expression of one,two, three or more RNA isoforms encoded by a gene is beneficial to theprevention and/or treatment of the disease, wherein the precursor RNAtranscript transcribed from the gene comprises a REMS, the methodscomprising administering to a patient in need thereof a compound ofFormula (I) or a form thereof, or a pharmaceutical compositioncomprising a compound of Formula (I) or a form thereof and apharmaceutically acceptable carrier, excipient or diluent. In oneembodiment, provided herein are methods for preventing and/or treating adisease in which the alteration (e.g., increase or decrease) in theexpression one, two, three or more RNA isoforms encoded by a gene, byway of nonlimiting example, disclosed in Table 6, infra, is beneficialto the prevention and/or treatment of the disease, the methodscomprising administering to a patient in need thereof a compound ofFormula (I) or a form thereof, or a pharmaceutical compositioncomprising a compound of Formula (I) or a form thereof and apharmaceutically acceptable carrier, excipient or diluent.

In another embodiment, provided herein are methods for preventing and/ortreating a disease in which the alteration (e.g., increase or decrease)in the expression one, two, three or more RNA isoforms encoded by agene, not disclosed in Tables 1-4, infra, is beneficial to theprevention and/or treatment of the disease, wherein the precursor RNAtranscript transcribed from the gene comprises a REMS, the methodscomprising administering to a patient in need thereof a compound ofFormula (I) or a form thereof, or a pharmaceutical compositioncomprising a compound of Formula (I) or a form thereof and apharmaceutically acceptable carrier, excipient or diluent.

In another embodiment, provided herein are methods for preventing and/ortreating a disease in which the alteration (e.g., increase or decrease)in the expression one, two, three or more RNA isoforms encoded by agene, not disclosed in International Patent Application No.PCT/US2014/071252 (International Publication No. WO 2015/105657 A1), isbeneficial to the prevention and/or treatment of the disease, whereinthe precursor RNA transcript transcribed from the gene comprises a REMS,the methods comprising administering to a patient in need thereof acompound of Formula (I) or a form thereof, or a pharmaceuticalcomposition comprising a compound of Formula (I) or a form thereof and apharmaceutically acceptable carrier, excipient or diluent. In anotherembodiment, provided herein are methods for preventing and/or treating adisease in which the alteration (e.g., increase or decrease) in theexpression one, two, three or more RNA isoforms encoded by a gene, notdisclosed in Table 6, infra, is beneficial to the prevention and/ortreatment of the disease, wherein the precursor RNA transcripttranscribed from the gene comprises a REMS, the methods comprisingadministering to a patient in need thereof a compound of Formula (I) ora form thereof, or a pharmaceutical composition comprising a compound ofFormula (I) or a form thereof and a pharmaceutically acceptable carrier,excipient or diluent.

In another embodiment, provided herein are methods for preventing and/ortreating a disease in which the alteration (e.g., increase or decrease)in the expression one, two, three or more RNA isoforms encoded byERGIC3, is beneficial to the prevention and/or treatment of the disease,the methods comprising administering to a patient in need thereof acompound of Formula (I) or a form thereof, or a pharmaceuticalcomposition comprising a compound of Formula (I) or a form thereof and apharmaceutically acceptable carrier, excipient or diluent. In a specificembodiment, one, two, three or more RNA isoforms encoded by ERGIC3 aredecreased following administration of a compound of Formula (I) or aform thereof and a pharmaceutically acceptable carrier, excipient ordiluent. See the example section for additional information regardingthe genes in Table 6.

In certain embodiments, a compound of Formula (I) is a compound ofFormula (II), Formula (III), Formula (IV), Formula (V), Formula (VI),Formula (VII), Formula (VIII), Formula (IX), Formula (X), Formula (XI),Formula (XII), Formula (XIII), or Formula (XIV) described infra. In someembodiments, a compound of Formula (I) is a compound selected from acompound described herein.

In another aspect, provided herein are methods for preventing and/ortreating a disease in which a change in the level of expression of one,two, three or more protein isoforms encoded by a gene is beneficial tothe prevention and/or treatment of the disease, wherein the precursorRNA transcript transcribed from the gene comprises a REMS, the methodscomprising administering to a patient in need thereof a compound ofFormula (I) or a form thereof, or a pharmaceutical compositioncomprising a compound of Formula (I) or a form thereof and apharmaceutically acceptable carrier, excipient or diluent. In oneembodiment, provided herein are methods for preventing and/or treating adisease in which the alteration (e.g., increase or decrease) in theexpression one, two, three or more protein isoforms encoded by a gene,by way of nonlimiting example, disclosed in Table 6, infra, isbeneficial to the prevention and/or treatment of the disease, themethods comprising administering to a patient in need thereof a compoundof Formula (I) or a form thereof, or a pharmaceutical compositioncomprising a compound of Formula (I) or a form thereof and apharmaceutically acceptable carrier, excipient or diluent.

In another embodiment, provided herein are methods for preventing and/ortreating a disease in which the alteration (e.g., increase or decrease)in the expression one, two, three or more protein isoforms encoded by agene, not disclosed in Tables 1-4, infra, is beneficial to theprevention and/or treatment of the disease, wherein the precursor RNAtranscript transcribed from the gene comprises a REMS, the methodscomprising administering to a patient in need thereof a compound ofFormula (I) or a form thereof, or a pharmaceutical compositioncomprising a compound of Formula (I) or a form thereof and apharmaceutically acceptable carrier, excipient or diluent. In anotherembodiment, provided herein are methods for preventing and/or treating adisease in which the alteration (e.g., increase or decrease) in theexpression one, two, three or more protein isoforms encoded by a gene,not disclosed in International Patent Application No. PCT/US2014/071252(International Publication No. WO 2015/105657 A1), is beneficial to theprevention and/or treatment of the disease, wherein the precursor RNAtranscript transcribed from the gene comprises a REMS, the methodscomprising administering to a patient in need thereof a compound ofFormula (I) or a form thereof, or a pharmaceutical compositioncomprising a compound of Formula (I) or a form thereof and apharmaceutically acceptable carrier, excipient or diluent. In anotherembodiment, provided herein are methods for preventing and/or treating adisease in which the alteration (e.g., increase or decrease) in theexpression one, two, three or more protein isoforms encoded by a gene,not disclosed in Table 6, infra, is beneficial to the prevention and/ortreatment of the disease, wherein the precursor RNA transcripttranscribed from the gene comprises a REMS, the methods comprisingadministering to a patient in need thereof a compound of Formula (I) ora form thereof, or a pharmaceutical composition comprising a compound ofFormula (I) or a form thereof and a pharmaceutically acceptable carrier,excipient or diluent.

In another embodiment, provided herein are methods for preventing and/ortreating a disease in which the alteration (e.g., increase or decrease)in the expression one, two, three or more protein isoforms encoded byERGIC3, is beneficial to the prevention and/or treatment of the disease,the methods comprising administering to a patient in need thereof acompound of Formula (I) or a form thereof, or a pharmaceuticalcomposition comprising a compound of Formula (I) or a form thereof and apharmaceutically acceptable carrier, excipient or diluent. In a specificembodiment, one, two, three or more RNA isoforms encoded by ERGIC3 aredecreased following administration of a compound of Formula (I) or aform thereof and a pharmaceutically acceptable carrier, excipient ordiluent. See the example section for additional information regardingthe genes in Table 6. In certain embodiments, a compound of Formula (I)is a compound of Formula (II), Formula (III), Formula (IV), Formula (V),Formula (VI), Formula (VII), Formula (VIII), Formula (IX), Formula (X),Formula (XI), Formula (XII), Formula (XIII), or Formula (XIV) describedinfra. In some embodiments, a compound of Formula (I) is a compoundselected from a compound described herein.

In another aspect, provided herein are artificial gene constructs. Inone embodiment, provided herein is an artificial gene constructcomprising DNA encoding exons, a 3′ splice site(s) and a branchpoint(s), wherein a nucleotide sequence encoding an exon, which isupstream of a nucleotide sequence encoding a branch point and anucleotide sequence encoding a 3′ splice site, is modified to introducea nucleotide sequence encoding a REMS. In another embodiment, providedherein is an artificial gene construct comprising DNA encoding exons andone, two or more introns, wherein a nucleotide sequence encoding a 5′splice site, which is upstream of a nucleotide sequence encoding abranch point and a nucleotide sequence encoding a 3′ splice site, ismodified to introduce a nucleotide sequence encoding a REMS. In anotherembodiment, provided herein is an artificial gene construct comprisingDNA encoding exons, a 5′ splice site(s), a 3′ splice site(s) and abranch point(s), wherein a nucleotide sequence encoding a 5′ splicesite, which is upstream of a nucleotide sequence encoding a 3′ splicesite, is modified to introduce a nucleotide sequence encoding a REMS. Incertain embodiments, the artificial gene construct encodes a therapeuticprotein. In some embodiments, the artificial gene construct encodes adetectable reporter protein. In a specific embodiment, the nucleotidesequence of the REMS introduced into the nucleotide sequence of theartificial gene construct comprises the sequence GAgtrngn (SEQ ID NO:5), wherein r is A or G and n is any nucleotide. In a specificembodiment, the nucleotide sequence encoding the REMS comprises thesequence ANGAgtrngn (SEQ ID NO: 7), wherein r is A or G and n or N isany nucleotide. In a further specific embodiment, the nucleotidesequence encoding the REMS comprises the sequence ANGAgtragt (SEQ ID NO:8), wherein r is A or G and N is any nucleotide. In various specificembodiments, the nucleotide sequence encoding the REMS is a nucleotidesequence encoding a non-endogenous REMS, i.e., not naturally found inthe DNA sequence of the artificial construct.

In certain embodiments, provided herein is a vector comprising theartificial gene construct described herein. In some embodiments,provided herein is a cell comprising an artificial gene constructdescribed herein or a vector comprising an artificial gene constructdescribed herein.

In another aspect, provided herein is a method of modulating the amountof a functional protein produced by a cell containing an artificial geneconstruct described herein. In one embodiment, provided herein is amethod of modulating the amount of a functional protein produced by acell containing an artificial gene construct described herein, themethod comprising contacting the cell with a compound of Formula (I) ora form thereof. In certain embodiments, the artificial gene constructencodes a therapeutic protein. In some embodiments, the artificial geneconstruct encodes a detectable reporter protein.

In another aspect, provided herein is a method of modulating the amountof a functional protein produced by a subject, wherein the subject is orwas administered an artificial gene construct described herein. In oneembodiment, provided herein is method of regulating the amount of afunctional protein produced by a subject, the method comprising: (a)administering an artificial gene construct or a vector comprising theartificial gene construct described herein to the subject; and (b)administering a compound of Formula (I) or a form thereof to thesubject. In another embodiment, provided herein is a method ofregulating the amount of a functional protein produced by a subject, themethod comprising administering a compound of Formula (I) or a formthereof to a subject carrying a gene containing a nucleotide sequenceencoding a REMS. In another embodiment, provided herein is a method ofregulating the amount of a functional protein produced by a subject, themethod comprising administering a compound of Formula (I) to thesubject, wherein the subject was previously administered an artificialgene construct described herein. In certain embodiments, the artificialgene construct encodes a therapeutic protein. In some embodiments, theartificial gene construct encodes a detectable reporter protein. Incertain embodiments, the subject is a non-human. In specificembodiments, the subject is a human.

In another aspect, provided herein is a method for modulating the amountof an RNA transcript produced from precursor RNA containing anon-endogenous recognition element for splicing modifier (REMS), themethod comprising contacting the precursor RNA with a compound ofFormula (I) or a form thereof, wherein the non-endogenous REMS comprisesthe sequence GAgurngn (SEQ ID NO: 1), wherein r is A or G and n is anynucleotide, and wherein Formula (I) is

-   -   wherein:    -   w₁ and w₅ are independently C—R_(a) or N;    -   w₂ is C—R_(b) or N;    -   w₃, w₄ and w₇ are independently C—R₁, C—R₂, C—R_(a) or N;    -   w₆ is C—R₁, C—R₂, C—R_(c) or N;    -   wherein one of w₃, w₄, w₆ and w₇ is C—R₁ and one other of w₃,        w₄, w₆ and w₇ is C—R₂, provided that,    -   when w₃ is C—R₁, then w₆ is C—R₂ and w₄ and w₇ are independently        C—R_(a) or N; or,    -   when w₃ is C—R₂, then w₆ is C—R₁ and w₄ and w₇ are independently        C—R_(a) or N; or,    -   when w₄ is C—R₁, then w₇ is C—R₂ and w₃ is C—R_(a) or N and w₆        is C—R_(c) or N; or,    -   when w₄ is C—R₂, then w₇ is C—R₁ and w₃ is C—R_(a) or N and w₆        is C—R_(c) or N; and,    -   wherein any one, two or three of w₁, w₂, w₃, w₄, w₅, w₆ and w₇        may optionally be N;    -   R₁ is C₁₋₈alkyl, amino, C₁₋₈alkyl-amino, (C₁₋₈alkyl)₂-amino,        C₁₋₈alkoxy-C₁₋₈alkyl-amino, (C₁₋₈alkoxy-C₁₋₈alkyl)₂-amino,        (C₁₋₈alkoxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino, amino-C₁₋₈alkyl,        C₁₋₈alkyl-amino-C₁₋₈alkyl, (C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,        C₁₋₈alkoxy-C₁₋₈alkyl-amino-C₁₋₈alkyl,        (C₁₋₈alkoxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,        (C₁₋₈alkoxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl,        amino-C₁₋₈alkyl-amino, (amino-C₁₋₈alkyl)₂-amino,        (amino-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        C₁₋₈alkyl-amino-C₁₋₈alkyl-amino,        (C₁₋₈alkyl-amino-C₁₋₈alkyl)₂-amino,        (C₁₋₈alkyl-amino-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        (C₁₋₈alkyl)₂-amino-C₁₋₈alkyl-amino,        [(C₁₋₈alkyl)₂-amino-C₁₋₈alkyl](C₁₋₈alkyl)amino,        amino-C₁₋₈alkoxy, C₁₋₈alkyl-amino-C₁₋₈alkoxy,        (C₁₋₈alkyl)₂-amino-C₁₋₈alkoxy,        C₁₋₈alkoxy-C₁₋₈alkyl-amino-C₁₋₈alkoxy,        C₁₋₈alkoxy-C₁₋₈alkyl-amino-C₁₋₈alkoxy,        (C₁₋₈alkoxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkoxy,        amino-C₂₋₈alkenyl, C₁₋₈alkyl-amino-C₂₋₈alkenyl,        (C₁₋₈alkyl)₂-amino-C₂₋₈alkenyl, amino-C₂₋₈alkynyl,        C₁₋₈alkyl-amino-C₂₋₈alkynyl, (C₁₋₈alkyl)₂-amino-C₂₋₈alkynyl,        halo-C₁₋₈alkyl-amino, (halo-C₁₋₈alkyl)₂-amino,        (halo-C₁₋₈alkyl)(C₁₋₈alkyl)amino, hydroxy-C₁₋₈alkyl,        hydroxy-C₁₋₈alkoxy-C₁₋₈alkyl, hydroxy-C₁₋₈alkyl-amino,        (hydroxy-C₁₋₈alkyl)₂-amino, (hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkyl,        (hydroxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,        (hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl,        hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkoxy,        (hydroxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkoxy,        (hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkoxy,        hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkyl-amino,        (hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkyl)₂-amino,        (hydroxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl-amino,        (hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        (hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl-amino,        [(hydroxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl](C₁₋₈alkyl)amino,        [(hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl](C₁₋₈alkyl)amino,        heterocyclyl, heterocyclyl-C₁₋₈alkyl, heterocyclyl-C₁₋₈alkoxy,        heterocyclyl-amino, (heterocyclyl)(C₁₋₈alkyl)amino,        heterocyclyl-amino-C₁₋₈alkyl, heterocyclyl-C₁₋₈alkyl-amino,        (heterocyclyl-C₁₋₈alkyl)₂-amino,        (heterocyclyl-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        heterocyclyl-C₁₋₈alkyl-amino-C₁₋₈alkyl,        (heterocyclyl-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,        (heterocyclyl-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl,        heterocyclyl-oxy, heterocyclyl-carbonyl,        heterocyclyl-carbonyl-oxy, C₃₋₁₄cycloalkyl,        aryl-C₁₋₈alkyl-amino, (aryl-C₁₋₈alkyl)₂-amino,        (aryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        aryl-C₁₋₈alkyl-amino-C₁₋₈alkyl,        (aryl-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,        (aryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl, heteroaryl,        heteroaryl-C₁₋₈alkyl, heteroaryl-C₁₋₈alkoxy, heteroaryl-amino,        heteroaryl-C₁₋₈alkyl-amino, (heteroaryl-C₁₋₈alkyl)₂-amino,        (heteroaryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        heteroaryl-C₁₋₈alkyl-amino-C₁₋₈alkyl,        (heteroaryl-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl or        (heteroaryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl;    -   wherein, each instance of heterocyclyl, C₃₋₁₄cycloalkyl, aryl        and heteroaryl is optionally substituted with one, two or three        R₃ substituents and optionally, with one additional R₄        substituent; or,    -   wherein, each instance of heterocyclyl, C₃₋₁₄cycloalkyl, aryl        and heteroaryl is optionally substituted with one, two, three or        four R₃ substituents;    -   R₂ is aryl, aryl-amino, aryl-amino-carbonyl, heterocyclyl,        heteroaryl or heteroaryl-amino;    -   wherein, each instance of aryl, heterocyclyl and heteroaryl is        optionally substituted with one, two or three R₆ substituents        and optionally, with one additional R₇ substituent;    -   R_(a) is, in each instance, independently selected from        hydrogen, halogen, C₁₋₈alkyl or deuterium;    -   R_(b) is hydrogen, halogen, C₁₋₈alkyl, C₁₋₈alkoxy or deuterium;    -   R_(c) is hydrogen, halogen, C₁₋₈alkyl or deuterium;    -   R₃ is, in each instance, independently selected from cyano,        halogen, hydroxy, oxo, C₁₋₈alkyl, halo-C₁₋₈alkyl,        C₁₋₈alkyl-carbonyl, C₁₋₈alkoxy, halo-C₁₋₈alkoxy,        C₁₋₈alkoxy-C₁₋₈alkyl, C₁₋₈alkoxy-carbonyl, amino,        C₁₋₈alkyl-amino, (C₁₋₈alkyl)₂-amino, amino-C₁₋₈alkyl,        C₁₋₈alkyl-amino-C₁₋₈alkyl, (C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,        amino-C₁₋₈alkyl-amino, C₁₋₈alkyl-amino-C₁₋₈alkyl-amino,        (C₁₋₈alkyl-amino-C₁₋₈alkyl)₂-amino,        (C₁₋₈alkyl)₂-amino-C₁₋₈alkyl-amino,        [(C₁₋₈alkyl)₂-amino-C₁₋₈alkyl]₂-amino,        (C₁₋₈alkyl-amino-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        [(C₁₋₈alkyl)₂-amino-C₁₋₈alkyl](C₁₋₈alkyl)amino,        C₁₋₈alkoxy-C₁₋₈alkyl-amino, (C₁₋₈alkoxy-C₁₋₈alkyl)₂-amino,        (C₁₋₈alkoxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        C₁₋₈alkyl-carbonyl-amino, C₁₋₈alkoxy-carbonyl-amino,        hydroxy-C₁₋₈alkyl, hydroxy-C₁₋₈alkoxy-C₁₋₈alkyl,        hydroxy-C₁₋₈alkyl-amino, (hydroxy-C₁₋₈alkyl)₂-amino or        (hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino;    -   R₄ is C₃₋₁₄cycloalkyl, C₃₋₁₄cycloalkyl-C₁₋₈alkyl,        C₃₋₁₄cycloalkyl-amino, aryl-C₁₋₈alkyl, aryl-C₁₋₈alkoxy-carbonyl,        aryl-sulfonyloxy-C₁₋₈alkyl, heterocyclyl or        heterocyclyl-C₁₋₈alkyl; wherein, each instance of        C₃₋₁₄cycloalkyl, aryl and heterocyclyl is optionally substituted        with one, two or three R₅ substituents;    -   R₅ is, in each instance, independently selected from halogen,        hydroxy, cyano, nitro, C₁₋₈alkyl, halo-C₁₋₈alkyl, C₁₋₈alkoxy,        halo-C₁₋₈alkoxy, amino, C₁₋₈alkyl-amino, (C₁₋₈alkyl)₂-amino or        C₁₋₈alkyl-thio;    -   R₆ is, in each instance, independently selected from halogen,        hydroxy, cyano, nitro, C₁₋₈alkyl, C₂₋₈alkenyl, halo-C₁₋₈alkyl,        hydroxy-C₁₋₈alkyl, C₁₋₈alkoxy, halo-C₁₋₈alkoxy,        C₁₋₈alkoxy-C₁₋₈alkyl, amino, C₁₋₈alkyl-amino, (C₁₋₈alkyl)₂-amino        or C₁₋₈alkyl-thio; and,    -   R₇ is C₃₋₁₄cycloalkyl, C₃₋₁₄cycloalkyl-oxy, aryl, heterocyclyl        or heteroaryl.

In another aspect, provided herein is a method of regulating the amountof a functional protein produced by a gene comprising a nucleotidesequence encoding a non-endogenous REMS in a subject, wherein thenucleotide sequence encoding a non-endogenous REMS comprises thesequence GAgtrngn (SEQ ID NO: 5), wherein r is A or G and n is anynucleotide, the method comprising administering a compound of Formula(I) to the subject, wherein Formula (I) is

-   -   wherein:    -   w₁ and w₅ are independently C—R_(a) or N;    -   w₂ is C—R_(b) or N;    -   w₃, w₄ and w₇ are independently C—R₁, C—R₂, C—R_(a) or N;    -   w₆ is C—R₁, C—R₂, C—R_(c) or N;    -   wherein one of w₃, w₄, w₆ and w₇ is C—R₁ and one other of w₃,        w₄, w₆ and w₇ is C—R₂, provided that,    -   when w₃ is C—R₁, then w₆ is C—R₂ and w₄ and w₇ are independently        C—R_(a) or N; or,    -   when w₃ is C—R₂, then w₆ is C—R₁ and w₄ and w₇ are independently        C—R_(a) or N; or,    -   when w₄ is C—R₁, then w₇ is C—R₂ and w₃ is C—R_(a) or N and w₆        is C—R_(c) or N; or,    -   when w₄ is C—R₂, then w₇ is C—R₁ and w₃ is C—R_(a) or N and w₆        is C—R_(c) or N; and,    -   wherein any one, two or three of w₁, w₂, w₃, w₄, w₅, w₆ and w₇        may optionally be N;    -   R₁ is C₁₋₈alkyl, amino, C₁₋₈alkyl-amino, (C₁₋₈alkyl)₂-amino,        C₁₋₈alkoxy-C₁₋₈alkyl-amino, (C₁₋₈alkoxy-C₁₋₈alkyl)₂-amino,        (C₁₋₈alkoxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino, amino-C₁₋₈alkyl,        C₁₋₈alkyl-amino-C₁₋₈alkyl, (C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,        C₁₋₈alkoxy-C₁₋₈alkyl-amino-C₁₋₈alkyl,        (C₁₋₈alkoxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,        (C₁₋₈alkoxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl,        amino-C₁₋₈alkyl-amino, (amino-C₁₋₈alkyl)₂-amino,        (amino-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        C₁₋₈alkyl-amino-C₁₋₈alkyl-amino,        (C₁₋₈alkyl-amino-C₁₋₈alkyl)₂-amino,        (C₁₋₈alkyl-amino-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        (C₁₋₈alkyl)₂-amino-C₁₋₈alkyl-amino,        [(C₁₋₈alkyl)₂-amino-C₁₋₈alkyl](C₁₋₈alkyl)amino,        amino-C₁₋₈alkoxy, C₁₋₈alkyl-amino-C₁₋₈alkoxy,        (C₁₋₈alkyl)₂-amino-C₁₋₈alkoxy,        C₁₋₈alkoxy-C₁₋₈alkyl-amino-C₁₋₈alkoxy,        C₁₋₈alkoxy-C₁₋₈alkyl-amino-C₁₋₈alkoxy,        (C₁₋₈alkoxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkoxy,        amino-C₂₋₈alkenyl, C₁₋₈alkyl-amino-C₂₋₈alkenyl,        (C₁₋₈alkyl)₂-amino-C₂₋₈alkenyl, amino-C₂₋₈alkynyl,        C₁₋₈alkyl-amino-C₂₋₈alkynyl, (C₁₋₈alkyl)₂-amino-C₂₋₈alkynyl,        halo-C₁₋₈alkyl-amino, (halo-C₁₋₈alkyl)₂-amino,        (halo-C₁₋₈alkyl)(C₁₋₈alkyl)amino, hydroxy-C₁₋₈alkyl,        hydroxy-C₁₋₈alkoxy-C₁₋₈alkyl, hydroxy-C₁₋₈alkyl-amino,        (hydroxy-C₁₋₈alkyl)₂-amino, (hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkyl,        (hydroxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,        (hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl,        hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkoxy,        (hydroxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkoxy,        (hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkoxy,        hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkyl-amino,        (hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkyl)₂-amino,        (hydroxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl-amino,        (hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        (hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl-amino,        [(hydroxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl](C₁₋₈alkyl)amino,        [(hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl](C₁₋₈alkyl)amino,        heterocyclyl, heterocyclyl-C₁₋₈alkyl, heterocyclyl-C₁₋₈alkoxy,        heterocyclyl-amino, (heterocyclyl)(C₁₋₈alkyl)amino,        heterocyclyl-amino-C₁₋₈alkyl, heterocyclyl-C₁₋₈alkyl-amino,        (heterocyclyl-C₁₋₈alkyl)₂-amino,        (heterocyclyl-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        heterocyclyl-C₁₋₈alkyl-amino-C₁₋₈alkyl,        (heterocyclyl-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,        (heterocyclyl-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl,        heterocyclyl-oxy, heterocyclyl-carbonyl,        heterocyclyl-carbonyl-oxy, C₃₋₁₄cycloalkyl,        aryl-C₁₋₈alkyl-amino, (aryl-C₁₋₈alkyl)₂-amino,        (aryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        aryl-C₁₋₈alkyl-amino-C₁₋₈alkyl,        (aryl-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,        (aryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl, heteroaryl,        heteroaryl-C₁₋₈alkyl, heteroaryl-C₁₋₈alkoxy, heteroaryl-amino,        heteroaryl-C₁₋₈alkyl-amino, (heteroaryl-C₁₋₈alkyl)₂-amino,        (heteroaryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        heteroaryl-C₁₋₈alkyl-amino-C₁₋₈alkyl,        (heteroaryl-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl or        (heteroaryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl;    -   wherein, each instance of heterocyclyl, C₃₋₁₄cycloalkyl, aryl        and heteroaryl is optionally substituted with one, two or three        R₃ substituents and optionally, with one additional R₄        substituent; or,    -   wherein, each instance of heterocyclyl, C₃₋₁₄cycloalkyl, aryl        and heteroaryl is optionally substituted with one, two, three or        four R₃ substituents;    -   R₂ is aryl, aryl-amino, aryl-amino-carbonyl, heterocyclyl,        heteroaryl or heteroaryl-amino;    -   wherein, each instance of aryl, heterocyclyl and heteroaryl is        optionally substituted with one, two or three R₆ substituents        and optionally, with one additional R₇ substituent;    -   R_(a) is, in each instance, independently selected from        hydrogen, halogen, C₁₋₈alkyl or deuterium;    -   R_(b) is hydrogen, halogen, C₁₋₈alkyl, C₁₋₈alkoxy or deuterium;    -   R_(c) is hydrogen, halogen, C₁₋₈alkyl or deuterium;    -   R₃ is, in each instance, independently selected from cyano,        halogen, hydroxy, oxo, C₁₋₈alkyl, halo-C₁₋₈alkyl,        C₁₋₈alkyl-carbonyl, C₁₋₈alkoxy, halo-C₁₋₈alkoxy,        C₁₋₈alkoxy-C₁₋₈alkyl, C₁₋₈alkoxy-carbonyl, amino,        C₁₋₈alkyl-amino, (C₁₋₈alkyl)₂-amino, amino-C₁₋₈alkyl,        C₁₋₈alkyl-amino-C₁₋₈alkyl, (C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,        amino-C₁₋₈alkyl-amino, C₁₋₈alkyl-amino-C₁₋₈alkyl-amino,        (C₁₋₈alkyl-amino-C₁₋₈alkyl)₂-amino,        (C₁₋₈alkyl)₂-amino-C₁₋₈alkyl-amino,        [(C₁₋₈alkyl)₂-amino-C₁₋₈alkyl]2-amino,        (C₁₋₈alkyl-amino-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        [(C₁₋₈alkyl)₂-amino-C₁₋₈alkyl](C₁₋₈alkyl)amino,        C₁₋₈alkoxy-C₁₋₈alkyl-amino, (C₁₋₈alkoxy-C₁₋₈alkyl)₂-amino,        (C₁₋₈alkoxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        C₁₋₈alkyl-carbonyl-amino, C₁₋₈alkoxy-carbonyl-amino,        hydroxy-C₁₋₈alkyl, hydroxy-C₁₋₈alkoxy-C₁₋₈alkyl,        hydroxy-C₁₋₈alkyl-amino, (hydroxy-C₁₋₈alkyl)₂-amino or        (hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino;    -   R₄ is C₃₋₁₄cycloalkyl, C₃₋₁₄cycloalkyl-C₁₋₈alkyl,        C₃₋₁₄cycloalkyl-amino, aryl-C₁₋₈alkyl, aryl-C₁₋₈alkoxy-carbonyl,        aryl-sulfonyloxy-C₁₋₈alkyl, heterocyclyl or        heterocyclyl-C₁₋₈alkyl; wherein, each instance of        C₃₋₁₄cycloalkyl, aryl and heterocyclyl is optionally substituted        with one, two or three R₅ substituents;    -   R₅ is, in each instance, independently selected from halogen,        hydroxy, cyano, nitro, C₁₋₈alkyl, halo-C₁₋₈alkyl, C₁₋₈alkoxy,        halo-C₁₋₈alkoxy, amino, C₁₋₈alkyl-amino, (C₁₋₈alkyl)₂-amino or        C₁₋₈alkyl-thio;    -   R₆ is, in each instance, independently selected from halogen,        hydroxy, cyano, nitro, C₁₋₈alkyl, C₂₋₈alkenyl, halo-C₁₋₈alkyl,        hydroxy-C₁₋₈alkyl, C₁₋₈alkoxy, halo-C₁₋₈alkoxy,        C₁₋₈alkoxy-C₁₋₈alkyl, amino, C₁₋₈alkyl-amino, (C₁₋₈alkyl)₂-amino        or C₁₋₈alkyl-thio; and,    -   R₇ is C₃₋₁₄cycloalkyl, C₃₋₁₄cycloalkyl-oxy, aryl, heterocyclyl        or heteroaryl.

In specific embodiments of the foregoing aspect, the gene is ABCA1,ABCB7, ABCC1, ABHD10, ABL2, ABLIM3, ACACA, ACADVL, ACAT2, ADAM12,ADAM15, ADAM17, ADAM33, AFF2, AGK, AGPAT3, AGPS, AHCYL2, AHDC1, AHRR,AJUBA, AK021888, AK310472, AKAP1, AKAP9, AKNA, ALCAM, ALDH4A1, AMPD2,ANK2, ANKFY1, ANKHD1-EIF4EBP3, ANKRD17, ANKS6, ANP32A, ANXA11, ANXA6,AP2B1, APAF1, APLP2, APP, APPL2, APTX, ARHGAP22, ARID1A, ARID2, ARMCX3,ASAP1, ASL, ASNS, ASPH, ATAD2B, ATF7IP, ATG9A, ATMIN, ATP2C1, ATXN3,AURKA, AXIN1, B4GALT2, BACE1, BAG2, BASP1, BC033281, BCAR3, BEND6,BICD1, BIN1, BNC1, BRD2, BRPF1, BSCL2, BTBD10, BZW1, C11orf30, C11orf73,C17orf76-AS1, C4orf27, C5orf24, C6orf48, C9orf69, CAB39, CALU, CAMKK1,CAPNS1, CASC3, CASP8AP2, CAV1, CCAR1, CCDC77, CCDC88A, CCDC92, CCT6A,CD276, CD46, CDC25B, CDC40, CDC42BPA, CDCA7, CDH11, CDH13, CDK11B,CDK16, CDKAL1, CEP68, CFLAR, CHD8, CIZ1, CLIC1, CLK4, CNOT1, COG1,COL12A1, COL1A1, COL6A1, COPS7B, CPEB2, CREB5, CRLS1, CRTAP, CSDE1,CSNK1A1, CTDSP2, CTNND1, CUL2, CUL4A, CUX1, CYB5B, CYBRD1, CYP51A1,DAB2, DACT1, DARS, DAXX, DCAF10, DCAF11, DCBLD2, DCUN1D4, DDAH1, DDAH2,DDHD2, DDR1, DDX39B, DDX42, DENND1A, DENND1B, DENND5A, DGCR2, DGKA,DHCR24, DHCR7, DHFR, DHX9, DIAPH1, DIAPH3, DIS3L, DKFZp434M1735, DKK3,DLC1, DNM2, DOCK1, DPP8, DSEL, DST, DSTN, EBF1, EEA1, EEF1A1, EFCAB14,EGR1, EHMT2, EIF2B3, EIF4G1, EIF4G2, EIF4G3, ELF2, ENG, ENPP2, ENSA,EPN1, EPT1, ERC1, ERGIC3, ETV5, EXO1, EXTL2, EYA3, FADS1, FADS2, FAF,FAM111A, FAM198B, FAM219A, FAM219B, FAM3C, FAM65A, FBXO10, FBXO18,FBXO31, FBXO34, FBXO9, FDFT1, FDPS, FER, FEZ1, FGD5-AS1, FGFRL1, FHOD3,FLII, FLNB, FN1, FNBP1, FOCAD, FOS, FOSB, FOSL1, FOXK1, FOXM1, FUS, FYN,GABPB1, GALC, GALNT1, GAS7, GBA2, GCFC2, GGCT, GHDC, GIGYF2, GJC1, GMIP,GNA13, GNAS, GNL3L, GOLGA2, GOLGA4, GOLGB1, GORASP1, GPR1, GPR89A,GPSM2, GREM1, GRK6, GSE1, GTF2H2B, HAS2, HAT1, HAUS3, HAUS6, HDAC7,HEG1, HLA-A, HLA-E, HLTF, HMGA1, HMGB1, HMGCR, HMGCS1, HMOX1, HNRNPR,HNRNPUL1, HP1BP3, HRH1, HSD17B12, HSD17B4, HTT, IARS, IDH1, IDI1,IGF2BP2, IL6ST, INHBA, INSIG1, IQCE, ITGAV, ITGB5, ITM2C, ITSN1, KANSL3,KCNK2, KIAA1033, KIAA1143, KIAA1199, KIAA1522, KIAA1524, KIAA1549,KIAA1715, KIF14, KIF2A, KIF3A, KLC1, KLC2, KLF6, KLHL7, KRT18, KRT19,KRT34, KRTAP2-3, LAMA2, LAMB1, LARP4, LARP7, LATS2, LDLR, LEMD3, LGALS8,LIMS1, LINC00341, LINC00657, LMAN2L, LMO7, LONP1, LOX, LRCH4, LRIG1,LRP8, LRRC8A, LSS, LTBR, LUC7L2, LZTS2, MADD, MAGED4, MAGED4B, MAN1A2,MAP4K4, MBD1, MBOAT7, MDM2, MED1, MEDAG, MEF2D, MEIS2, MEMO1, MEPCE,MFGE8, MICAL2, MINPP1, MKL1, MKLN1, MKNK2, MLLT4, MLST8, MMAB, MMS19,MMS22L, MPPE1, MPZL1, MRPL3, MSANTD3, MSC, MSH2, MSH6, MSL3, MSMO1,MSRB3, MTAP, MTERFD1, MTHFD1L, MTMR9, MTRR, MUM1, MVD, MVK, MYADM, MYLK,MYO1D, MYO9B, MYOF, NAA35, NADK, NASP, NAV1, NAV2, NCOA1, NCOA3, NCOA4,NCSTN, NELFA, NEO1, NEURL1B, NF2, NFE2L1, NFX1, NID1, NID2, NIPA1,NKX3-1, NOL10, NOMO3, NPEPPS, NRD1, NREP, NRG1, NSUN4, NT5C2, NT5E,NTNG1, NUDT4, NUP153, NUP35, NUP50, NUPL1, NUSAP1, ODF2, OS9, OSBPL6,OSMR, P4HA1, P4HB, PABPC1, PAK4, PAPD4, PARD3, PARN, PARP14, PARP4,PARVB, PCBP2, PCBP4, PCDHGB3, PCGF3, PCM1, PCMTD2, PCNXL2, PCSK9, PDE4A,PDE7A, PDLIM7, PDXDC1, PEPD, PEX5, PFKP, PHF19, PHF8, PHRF1, PHTF2,PI4K2A, PIEZO1, PIGU, PIK3C2B, PITPNA, PITPNB, PITPNM1, PLAU, PLEC,PLEKHB2, PLSCR3, PLXNB2, PLXNC1, PMS1, POLE3, POLR3D, POSTN, POU2F1,PPAPDC1A, PPARA, PPHLN1, PPIP5K1, PPP1R12A, PPP6R1, PPP6R2, PRKACB,PRKDC, PRMT1, PRNP, PRSS23, PSMA4, PSMC1, PSMD6, PTK2B, PTPN14, PUF60,PUS7, PVR, PXN, QKI, RAB23, RAB2B, RAB34, RAD1, RAD23B, RALB, RAP1A,RAP1GDS1, RARG, RASSF8, RBCK1, RBFOX2, RBM10, RCC1, RFTN1, RFWD2, RGS10,RGS3, RIF1, RNF14, RNF19A, RNF38, RNFT1, RPL10, RPS6KC1, RRBP1, RWDD4,SAMD9, SAMD9L, SAR1A, SART3, SCAF4, SCAF8, SCD, SCLT1, SCO1, SDCBP,SEC14L1, SEC22A, SEC24B, SEC61A1, SEPT9, SERPINE2, SF1, SGOL2, SH3RF1,SKIL, SLC25A17, SLC39A3, SLC41A1, SLC4A4, SLC7A6, SLC7A8, SMARCA4,SMARCC2, SMC4, SMC6, SMCHD1, SMG1, SMN2, SMPD4, SMYD3, SMYD5, SNAP23,SNHG16, SNX14, SOCS2, SON, SOS2, SPATA20, SPATS2, SPG20, SPRED2, SQLE,SQRDL, SQSTM1, SRCAP, SREBF1, SREK1, SRSF3, STARD4, STAT1, STAT3, STAU1,STC2, STEAP2, STRIP1, STRN3, STX16, SUPT20H, SYNE1, SYNE2, SYT15, SYTL2,TACC1, TAF2, TANC2, TARBP1, TARS, TBC1D15, TBL2, TCF7L2, TENC1, TENM2,TEP1, TET3, TFCP2, TGFBI, TGFBR1, TGFBRAP1, THADA, THAP4, THRB, TIMP2,TJP2, TLE3, TLK1, TMEM154, TMEM47, TMEM63A, TNC, TNFAIP3, TNFRSF12A,TNIP1, TNKS1BP1, TNPO3, TNS1, TNS3, TOE1, TOMM40, TOMM5, TOPORS,TP53INP1, TRAF3, TRAK1, TRAPPC12, TRIB1, TRIM2, TRIM23, TRIM26, TRIM28,TRIM65, TRMT1L, TRPS1, TSC2, TSHZ1, TSPAN2, TTC7A, TUBB2C, TUBB3, TXNL1,TXNRD1, U2SURP, UBAP2L, UBE2G2, UBE2V1, UBQLN4, UCHL5, UHMK1, UHRF1BP1L,UNC5B, USP19, USP7, VANGL1, VARS2, VCL, VIPAS39, VPS13A, VPS29, VPS51,VWA8, WDR19, WDR37, WDR48, WIPF1, WNT5B, WSB1, WWTR1, XIAP, XRN2, YAP1,YES1, YPEL5, YTHDF3, Z24749, ZAK, ZBTB10, ZBTB24, ZBTB7A, ZC3H12C,ZC3H14, ZC3H18, ZCCHC11, ZEB1, ZEB2, ZFAND1, ZFAND5, ZHX3, ZMIZ1, ZMYM2,ZNF12, ZNF148, ZNF219, ZNF227, ZNF24, ZNF268, ZNF28, ZNF281, ZNF335,ZNF37A, ZNF37BP, ZNF395, ZNF583, ZNF621, ZNF652, ZNF655, ZNF674, ZNF74,ZNF764, ZNF778, ZNF780A, ZNF827, ZNF839 or ZNF91.

In another aspect, provide herein is a method of modulating the amountof a functional protein produced by a cell containing the artificialgene construct as described above, the method comprising contacting thecell with a compound of Formula (I) or a form thereof, wherein Formula(I) is

-   -   wherein:    -   w₁ and w₅ are independently C—R_(a) or N;    -   w₂ is C—R_(b) or N;    -   w₃, w₄ and w₇ are independently C—R₁, C—R₂, C—R_(a) or N;    -   w₆ is C—R₁, C—R₂, C—R_(c) or N;    -   wherein one of w₃, w₄, w₆ and w₇ is C—R₁ and one other of w₃,        w₄, w₆ and w₇ is C—R₂, provided that,    -   when w₃ is C—R₁, then w₆ is C—R₂ and w₄ and w₇ are independently        C—R_(a) or N; or,    -   when w₃ is C—R₂, then w₆ is C—R₁ and w₄ and w₇ are independently        C—R_(a) or N; or,    -   when w₄ is C—R₁, then w₇ is C—R₂ and w₃ is C—R_(a) or N and w₆        is C—R_(c) or N; or,    -   when w₄ is C—R₂, then w₇ is C—R₁ and w₃ is C—R_(a) or N and w₆        is C—R_(c) or N; and,    -   wherein any one, two or three of w₁, w₂, w₃, w₄, w₅, w₆ and w₇        may optionally be N;    -   R₁ is C₁₋₈alkyl, amino, C₁₋₈alkyl-amino, (C₁₋₈alkyl)₂-amino,        C₁₋₈alkoxy-C₁₋₈alkyl-amino, (C₁₋₈alkoxy-C₁₋₈alkyl)₂-amino,        (C₁₋₈alkoxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino, amino-C₁₋₈alkyl,        C₁₋₈alkyl-amino-C₁₋₈alkyl, (C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,        C₁₋₈alkoxy-C₁₋₈alkyl-amino-C₁₋₈alkyl,        (C₁₋₈alkoxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,        (C₁₋₈alkoxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl,        amino-C₁₋₈alkyl-amino, (amino-C₁₋₈alkyl)₂-amino,        (amino-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        C₁₋₈alkyl-amino-C₁₋₈alkyl-amino,        (C₁₋₈alkyl-amino-C₁₋₈alkyl)₂-amino,        (C₁₋₈alkyl-amino-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        (C₁₋₈alkyl)₂-amino-C₁₋₈alkyl-amino,        [(C₁₋₈alkyl)₂-amino-C₁₋₈alkyl](C₁₋₈alkyl)amino,        amino-C₁₋₈alkoxy, C₁₋₈alkyl-amino-C₁₋₈alkoxy,        (C₁₋₈alkyl)₂-amino-C₁₋₈alkoxy,        C₁₋₈alkoxy-C₁₋₈alkyl-amino-C₁₋₈alkoxy,        C₁₋₈alkoxy-C₁₋₈alkyl-amino-C₁₋₈alkoxy,        (C₁₋₈alkoxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkoxy,        amino-C₂₋₈alkenyl, C₁₋₈alkyl-amino-C₂₋₈alkenyl,        (C₁₋₈alkyl)₂-amino-C₂₋₈alkenyl, amino-C₂₋₈alkynyl,        C₁₋₈alkyl-amino-C₂₋₈alkynyl, (C₁₋₈alkyl)₂-amino-C₂₋₈alkynyl,        halo-C₁₋₈alkyl-amino, (halo-C₁₋₈alkyl)₂-amino,        (halo-C₁₋₈alkyl)(C₁₋₈alkyl)amino, hydroxy-C₁₋₈alkyl,        hydroxy-C₁₋₈alkoxy-C₁₋₈alkyl, hydroxy-C₁₋₈alkyl-amino,        (hydroxy-C₁₋₈alkyl)₂-amino, (hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkyl,        (hydroxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,        (hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl,        hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkoxy,        (hydroxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkoxy,        (hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkoxy,        hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkyl-amino,        (hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkyl)₂-amino,        (hydroxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl-amino,        (hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        (hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl-amino,        [(hydroxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl](C₁₋₈alkyl)amino,        [(hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl](C₁₋₈alkyl)amino,        heterocyclyl, heterocyclyl-C₁₋₈alkyl, heterocyclyl-C₁₋₈alkoxy,        heterocyclyl-amino, (heterocyclyl)(C₁₋₈alkyl)amino,        heterocyclyl-amino-C₁₋₈alkyl, heterocyclyl-C₁₋₈alkyl-amino,        (heterocyclyl-C₁₋₈alkyl)₂-amino,        (heterocyclyl-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        heterocyclyl-C₁₋₈alkyl-amino-C₁₋₈alkyl,        (heterocyclyl-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,        (heterocyclyl-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl,        heterocyclyl-oxy, heterocyclyl-carbonyl,        heterocyclyl-carbonyl-oxy, C₃₋₁₄cycloalkyl,        aryl-C₁₋₈alkyl-amino, (aryl-C₁₋₈alkyl)₂-amino,        (aryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        aryl-C₁₋₈alkyl-amino-C₁₋₈alkyl,        (aryl-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,        (aryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl, heteroaryl,        heteroaryl-C₁₋₈alkyl, heteroaryl-C₁₋₈alkoxy, heteroaryl-amino,        heteroaryl-C₁₋₈alkyl-amino, (heteroaryl-C₁₋₈alkyl)₂-amino,        (heteroaryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        heteroaryl-C₁₋₈alkyl-amino-C₁₋₈alkyl,        (heteroaryl-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl or        (heteroaryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl;    -   wherein, each instance of heterocyclyl, C₃₋₁₄cycloalkyl, aryl        and heteroaryl is optionally substituted with one, two or three        R₃ substituents and optionally, with one additional R₄        substituent; or,    -   wherein, each instance of heterocyclyl, C₃₋₁₄cycloalkyl, aryl        and heteroaryl is optionally substituted with one, two, three or        four R₃ substituents;    -   R₂ is aryl, aryl-amino, aryl-amino-carbonyl, heterocyclyl,        heteroaryl or heteroaryl-amino;    -   wherein, each instance of aryl, heterocyclyl and heteroaryl is        optionally substituted with one, two or three R₆ substituents        and optionally, with one additional R₇ substituent;    -   R_(a) is, in each instance, independently selected from        hydrogen, halogen, C₁₋₈alkyl or deuterium;    -   R_(b) is hydrogen, halogen, C₁₋₈alkyl, C₁₋₈alkoxy or deuterium;    -   R_(c) is hydrogen, halogen, C₁₋₈alkyl or deuterium;    -   R₃ is, in each instance, independently selected from cyano,        halogen, hydroxy, oxo, C₁₋₈alkyl, halo-C₁₋₈alkyl,        C₁₋₈alkyl-carbonyl, C₁₋₈alkoxy, halo-C₁₋₈alkoxy,        C₁₋₈alkoxy-C₁₋₈alkyl, C₁₋₈alkoxy-carbonyl, amino,        C₁₋₈alkyl-amino, (C₁₋₈alkyl)₂-amino, amino-C₁₋₈alkyl,        C₁₋₈alkyl-amino-C₁₋₈alkyl, (C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,        amino-C₁₋₈alkyl-amino, C₁₋₈alkyl-amino-C₁₋₈alkyl-amino,        (C₁₋₈alkyl-amino-C₁₋₈alkyl)₂-amino,        (C₁₋₈alkyl)₂-amino-C₁₋₈alkyl-amino,        [(C₁₋₈alkyl)₂-amino-C₁₋₈alkyl]2-amino,        (C₁₋₈alkyl-amino-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        [(C₁₋₈alkyl)₂-amino-C₁₋₈alkyl](C₁₋₈alkyl)amino,        C₁₋₈alkoxy-C₁₋₈alkyl-amino, (C₁₋₈alkoxy-C₁₋₈alkyl)₂-amino,        (C₁₋₈alkoxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        C₁₋₈alkyl-carbonyl-amino, C₁₋₈alkoxy-carbonyl-amino,        hydroxy-C₁₋₈alkyl, hydroxy-C₁₋₈alkoxy-C₁₋₈alkyl,        hydroxy-C₁₋₈alkyl-amino, (hydroxy-C₁₋₈alkyl)₂-amino or        (hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino;    -   R₄ is C₃₋₁₄cycloalkyl, C₃₋₁₄cycloalkyl-C₁₋₈alkyl,        C₃₋₁₄cycloalkyl-amino, aryl-C₁₋₈alkyl, aryl-C₁₋₈alkoxy-carbonyl,        aryl-sulfonyloxy-C₁₋₈alkyl, heterocyclyl or        heterocyclyl-C₁₋₈alkyl; wherein, each instance of        C₃₋₁₄cycloalkyl, aryl and heterocyclyl is optionally substituted        with one, two or three R₅ substituents;    -   R₅ is, in each instance, independently selected from halogen,        hydroxy, cyano, nitro, C₁₋₈alkyl, halo-C₁₋₈alkyl, C₁₋₈alkoxy,        halo-C₁₋₈alkoxy, amino, C₁₋₈alkyl-amino, (C₁₋₈alkyl)₂-amino or        C₁₋₈alkyl-thio;    -   R₆ is, in each instance, independently selected from halogen,        hydroxy, cyano, nitro, C₁₋₈alkyl, C₂₋₈alkenyl, halo-C₁₋₈alkyl,        hydroxy-C₁₋₈alkyl, C₁₋₈alkoxy, halo-C₁₋₈alkoxy,        C₁₋₈alkoxy-C₁₋₈alkyl, amino, C₁₋₈alkyl-amino, (C₁₋₈alkyl)₂-amino        or C₁₋₈alkyl-thio; and,    -   R₇ is C₃₋₁₄cycloalkyl, C₃₋₁₄cycloalkyl-oxy, aryl, heterocyclyl        or heteroaryl.

In a specific embodiment, the nucleotide sequence encoding the REMScomprises the sequence ANGAgtrngn (SEQ ID NO: 7), wherein r is A or Gand n or N is any nucleotide. In a further specific embodiment, thenucleotide sequence encoding the REMS comprises the sequence ANGAgtragt(SEQ ID NO: 8), wherein r is A or G and N is any nucleotide. In variousspecific embodiments, the nucleotide sequence encoding the REMS is anucleotide sequence encoding a non-endogenous REMS, i.e., not naturallyfound in the DNA sequence of the artificial construct.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-1D. Representative schematics of splicing mediated by REMS.5′SS is 5′ splice site. 3′SS is 3′ splice site. Splicing events mediatedby REMS are illustrated by solid lines, splicing events not mediated byREMS are illustrated by dashed lines.

FIGS. 2A and 2B. SMN1 mutant C6 showed compound-dependent increasedinclusion of exon 7 (FIG. 2A). The secondary structure of TSL2 (terminalstem loop 2) in SMN2. (Sequence shown is AUUCCUUAAAUUAAGGAguaagu (SEQ IDNO: 118) (FIG. 2B)).

FIGS. 3A and 3B. Exemplary mutations introduced into TSL2 in SMN2.(Sequences shown are AUUCCAUAAAUUAUGGAguaagu (SEQ ID NO: 119) andACUUACCUG (SEQ ID NO: 120) (FIG. 3A)). SMN2 T43A51T mutant was resistantto compound-dependent inclusion of exon 7 (FIG. 3B).

FIGS. 4A and 4B. The resistance of SMN2 T43A51T mutant tocompound-dependent inclusion of exon 7 is driven by the A51 mutation.

FIGS. 5A and 5B. REMS of SMN2 (sequence is AGGAguaagu (SEQ ID NO: 88)(FIG. 5A). Additional mutants confirmed the functional role of the REMSin SMN2 (FIG. 5B).

FIG. 6. Mutations outside of the REMS does not affect the activity ofthe compound on splicing.

FIGS. 7A-7L. Testing of alternative splicing in different genesconfirmed the existence of a consensus REMS.

DETAILED DESCRIPTION Recognition Element for Splicing Modifier (REMS)

In one aspect, provided herein is a recognition element for splicingmodifier (otherwise referred to as “REMS”) that plays a role in therecognition of a compound described herein. In a specific embodiment,the REMS has the nucleotide sequence GAgurngn (SEQ ID NO: 1) at the RNAlevel, wherein r is A or G (i.e., a purine nucleotide) and n is anynucleotide. In another specific embodiment, the REMS has the nucleotidesequence GAguragu (SEQ ID NO: 2) at the RNA level, wherein r is A or G.In another specific embodiment, the REMS has the nucleotide sequenceANGAgurngn (SEQ ID NO: 3) at the RNA level, wherein r is A or G (i.e., apurine nucleotide) and n or N is any nucleotide. In a preferredembodiment, the REMS has the nucleotide sequence ANGAguragu (SEQ ID NO:4) at the RNA level, wherein r is A or G and N is any nucleotide.

In the context of DNA, in a specific embodiment, the nucleotide sequenceencoding a REMS has the sequence GAgtrngn (SEQ ID NO: 5), wherein r is Aor G (i.e., a purine nucleotide) and n is any nucleotide. In anotherspecific embodiment, in the context of DNA, the nucleotide sequenceencoding a REMS has the sequence GAgtragt (SEQ ID NO: 6), wherein r is Aor G. In a specific embodiment, in the context of DNA, the nucleotidesequence encoding a REMS has the sequence ANGAgtrngn (SEQ ID NO: 7),wherein r is A or G (i.e., a purine nucleotide) and n or N is anynucleotide. In a preferred embodiment, in the context of DNA, thenucleotide sequence encoding a REMS has the sequence ANGAgtragt (SEQ IDNO: 8), wherein r is A or G and N is any nucleotide.

A REMS can be part of an endogenous RNA or can be introduced into an RNAsequence that does not naturally contain the REMS sequence (in whichcase, the introduced REMS is a non-endogenous REMS, i.e., a REMS notnaturally present in the corresponding RNA. A nucleotide sequenceencoding REMS can also be part of an endogenous DNA sequence, or anucleotide sequence encoding a REMS can be introduced into a DNAsequence that does not naturally contain the nucleotide sequenceencoding the REMS introduced.

In a specific embodiment, the REMS is located in the 5′ splice site. Incertain embodiments, the REMS is located within an exon, such as inFoxM1 exon 7a. Without being bound by any theory or mechanism, it isbelieved that compounds described herein increase the affinity of theinteraction between U1 snRNP and the nucleotides ANGA (SEQ ID NO: 9) ofthe REMS. This belief is based, in part, on the recognition that REMScomprises the U1 snRNP binding site.

In FIG. 1D, the REMS is located in the 5′ splice site of a precursorRNA. In the presence of a compound described herein, the nucleotidesbetween the REMS in the 5′ splice site and 3′ splice site of a precursorRNA are (except the nucleotides of the exon) removed and the exons ofthe precursor RNA are spliced together. In FIG. 1B, the REMS is locatedwithin an exon in a precursor RNA. In the presence of a compounddescribed herein, the nucleotides between the REMS and the 3′ splicesite of a precursor RNA (except the nucleotides GA or ANGA) are removedand the remaining portions of the precursor RNA are spliced together,which may result in an RNA transcript with a truncated open readingframe or internal deletions within the open reading frame.

In one embodiment, a precursor RNA transcript comprises three exons andtwo introns, wherein a REMS is present endogenously or introduced intothe 5′ splice site of the exon 2-intron 2 boundary of the RNAtranscript. In the absence of a compound described herein, some degreeof exon 2 skipping will occur and two mRNAs will be produced, e1e2e3 ande1e3. When compound is added, the balance between the two mRNAs producedis shifted so that more e1e2e3 and less e1e3 mRNA is produced. See FIGS.1A-1D.

In another embodiment, a precursor RNA transcript comprises two exonsand one intron, wherein a REMS is present endogenously or introducedinto the 5′splice site of the exon 1-intron 1 boundary of the RNAtranscript. In the absence of a compound described herein, some degreeof inhibition of splicing altogether will occur and two RNA productswill be produced—pre-mRNA e1i1e2, which is usually unstable and degradedand, thus, usually not translated so no functional protein is produced,and e1e2 mRNA. When compound is added, the balance between the two RNAproducts is shifted so that more e1e2 and less e1i1e2 is produced. SeeFIGS. 1A-1D.

In another embodiment, a precursor RNA transcript comprises a REMSinside an exon (e.g., FOXM1 exon 7a). In this situation, in the absenceof a compound described herein, the splicing outcome is driven by thedistal 5′ splice site and the 5′splice site mediates whole exonsplicing. However, when a compound described herein is present, splicingat the REMS is induced and inclusion of a shorter exon results. See FIG.1B.

When a REMS is introduced into an RNA sequence, the splicing outcomewill be governed by the presence/absence of an upstream 5′ splicesite(s), upstream 3′ splice sites, and downstream 3′ splice site(s). SeeFIGS. 1A and 1C.

When a REMS is introduced into an RNA sequence, the splicing outcomewill be governed by the presence/absence of an upstream 5′ splicesite(s), upstream 3′ splice sites, and downstream 3′ splice site(s) andendogenous splicing control sequences.

Compounds

Provided herein are compounds of Formula (I) for use in the methodsdescribed herein:

-   -   or a form thereof, wherein:    -   w₁ and w₅ are independently C—R_(a) or N;    -   w₂ is C—R_(b) or N;    -   w₃, w₄ and w₇ are independently C—R₁, C—R₂, C—R_(a) or N;    -   w₆ is C—R₁, C—R₂, C—R_(c) or N;    -   wherein one of w₃, w₄, w₆ and w₇ is C—R₁ and one other of w₃,        w₄, w₆ and w₇ is C—R₂, provided that,    -   when w₃ is C—R₁, then w₆ is C—R₂ and w₄ and w₇ are independently        C—R_(a) or N; or,    -   when w₃ is C—R₂, then w₆ is C—R₁ and w₄ and w₇ are independently        C—R_(a) or N; or,    -   when w₄ is C—R₁, then w₇ is C—R₂ and w₃ is C—R_(a) or N and w₆        is C—R_(c) or N; or,    -   when w₄ is C—R₂, then w₇ is C—R₁ and w₃ is C—R_(a) or N and w₆        is C—R_(c) or N; and,    -   wherein any one, two or three of w₁, w₂, w₃, w₄, w₅, w₆ and w₇        may optionally be N;    -   R₁ is C₁₋₈alkyl, amino, C₁₋₈alkyl-amino, (C₁₋₈alkyl)₂-amino,        C₁₋₈alkoxy-C₁₋₈alkyl-amino, (C₁₋₈alkoxy-C₁₋₈alkyl)₂-amino,        (C₁₋₈alkoxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino, amino-C₁₋₈alkyl,        C₁₋₈alkyl-amino-C₁₋₈alkyl, (C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,        C₁₋₈alkoxy-C₁₋₈alkyl-amino-C₁₋₈alkyl,        (C₁₋₈alkoxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,        (C₁₋₈alkoxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl,        amino-C₁₋₈alkyl-amino, (amino-C₁₋₈alkyl)₂-amino,        (amino-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        C₁₋₈alkyl-amino-C₁₋₈alkyl-amino,        (C₁₋₈alkyl-amino-C₁₋₈alkyl)₂-amino,        (C₁₋₈alkyl-amino-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        (C₁₋₈alkyl)₂-amino-C₁₋₈alkyl-amino,        [(C₁₋₈alkyl)₂-amino-C₁₋₈alkyl](C₁₋₈alkyl)amino,        amino-C₁₋₈alkoxy, C₁₋₈alkyl-amino-C₁₋₈alkoxy,        (C₁₋₈alkyl)₂-amino-C₁₋₈alkoxy,        C₁₋₈alkoxy-C₁₋₈alkyl-amino-C₁₋₈alkoxy,        C₁₋₈alkoxy-C₁₋₈alkyl-amino-C₁₋₈alkoxy,        (C₁₋₈alkoxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkoxy,        amino-C₂₋₈alkenyl, C₁₋₈alkyl-amino-C₂₋₈alkenyl,        (C₁₋₈alkyl)₂-amino-C₂₋₈alkenyl, amino-C₂₋₈alkynyl,        C₁₋₈alkyl-amino-C₂₋₈alkynyl, (C₁₋₈alkyl)₂-amino-C₂₋₈alkynyl,        halo-C₁₋₈alkyl-amino, (halo-C₁₋₈alkyl)₂-amino,        (halo-C₁₋₈alkyl)(C₁₋₈alkyl)amino, hydroxy-C₁₋₈alkyl,        hydroxy-C₁₋₈alkoxy-C₁₋₈alkyl, hydroxy-C₁₋₈alkyl-amino,        (hydroxy-C₁₋₈alkyl)₂-amino, (hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkyl,        (hydroxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,        (hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl,        hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkoxy,        (hydroxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkoxy,        (hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkoxy,        hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkyl-amino,        (hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkyl)₂-amino,        (hydroxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl-amino,        (hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        (hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl-amino,        [(hydroxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl](C₁₋₈alkyl)amino,        [(hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl](C₁₋₈alkyl)amino,        heterocyclyl, heterocyclyl-C₁₋₈alkyl, heterocyclyl-C₁₋₈alkoxy,        heterocyclyl-amino, (heterocyclyl)(C₁₋₈alkyl)amino,        heterocyclyl-amino-C₁₋₈alkyl, heterocyclyl-C₁₋₈alkyl-amino,        (heterocyclyl-C₁₋₈alkyl)₂-amino,        (heterocyclyl-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        heterocyclyl-C₁₋₈alkyl-amino-C₁₋₈alkyl,        (heterocyclyl-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,        (heterocyclyl-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl,        heterocyclyl-oxy, heterocyclyl-carbonyl,        heterocyclyl-carbonyl-oxy, C₃₋₁₄cycloalkyl,        aryl-C₁₋₈alkyl-amino, (aryl-C₁₋₈alkyl)₂-amino,        (aryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        aryl-C₁₋₈alkyl-amino-C₁₋₈alkyl,        (aryl-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,        (aryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl, heteroaryl,        heteroaryl-C₁₋₈alkyl, heteroaryl-C₁₋₈alkoxy, heteroaryl-amino,        heteroaryl-C₁₋₈alkyl-amino, (heteroaryl-C₁₋₈alkyl)₂-amino,        (heteroaryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        heteroaryl-C₁₋₈alkyl-amino-C₁₋₈alkyl,        (heteroaryl-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl or        (heteroaryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl;    -   wherein, each instance of heterocyclyl, C₃₋₁₄cycloalkyl, aryl        and heteroaryl is optionally substituted with one, two or three        R₃ substituents and optionally, with one additional R₄        substituent; or,    -   wherein, each instance of heterocyclyl, C₃₋₁₄cycloalkyl, aryl        and heteroaryl is optionally substituted with one, two, three or        four R₃ substituents;    -   R₂ is aryl, aryl-amino, aryl-amino-carbonyl, heterocyclyl,        heteroaryl or heteroaryl-amino;    -   wherein, each instance of aryl, heterocyclyl and heteroaryl is        optionally substituted with one, two or three R₆ substituents        and optionally, with one additional R₇ substituent;    -   R_(a) is, in each instance, independently selected from        hydrogen, halogen, C₁₋₈alkyl or deuterium;    -   R_(b) is hydrogen, halogen, C₁₋₈alkyl, C₁₋₈alkoxy or deuterium;    -   R_(c) is hydrogen, halogen, C₁₋₈alkyl or deuterium;    -   R₃ is, in each instance, independently selected from cyano,        halogen, hydroxy, oxo, C₁₋₈alkyl, halo-C₁₋₈alkyl,        C₁₋₈alkyl-carbonyl, C₁₋₈alkoxy, halo-C₁₋₈alkoxy,        C₁₋₈alkoxy-C₁₋₈alkyl, C₁₋₈alkoxy-carbonyl, amino,        C₁₋₈alkyl-amino, (C₁₋₈alkyl)₂-amino, amino-C₁₋₈alkyl,        C₁₋₈alkyl-amino-C₁₋₈alkyl, (C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,        amino-C₁₋₈alkyl-amino, C₁₋₈alkyl-amino-C₁₋₈alkyl-amino,        (C₁₋₈alkyl-amino-C₁₋₈alkyl)₂-amino,        (C₁₋₈alkyl)₂-amino-C₁₋₈alkyl-amino,        [(C₁₋₈alkyl)₂-amino-C₁₋₈alkyl]₂-amino,        (C₁₋₈alkyl-amino-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        [(C₁₋₈alkyl)₂-amino-C₁₋₈alkyl](C₁₋₈alkyl)amino,        C₁₋₈alkoxy-C₁₋₈alkyl-amino, (C₁₋₈alkoxy-C₁₋₈alkyl)₂-amino,        (C₁₋₈alkoxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino,        C₁₋₈alkyl-carbonyl-amino, C₁₋₈alkoxy-carbonyl-amino,        hydroxy-C₁₋₈alkyl, hydroxy-C₁₋₈alkoxy-C₁₋₈alkyl,        hydroxy-C₁₋₈alkyl-amino, (hydroxy-C₁₋₈alkyl)₂-amino or        (hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino;    -   R₄ is C₃₋₁₄cycloalkyl, C₃₋₁₄cycloalkyl-C₁₋₈alkyl,        C₃₋₁₄cycloalkyl-amino, aryl-C₁₋₈alkyl, aryl-C₁₋₈alkoxy-carbonyl,        aryl-sulfonyloxy-C₁₋₈alkyl, heterocyclyl or        heterocyclyl-C₁₋₈alkyl; wherein, each instance of        C₃₋₁₄cycloalkyl, aryl and heterocyclyl is optionally substituted        with one, two or three R₅ substituents;    -   R₅ is, in each instance, independently selected from halogen,        hydroxy, cyano, nitro, C₁₋₈alkyl, halo-C₁₋₈alkyl, C₁₋₈alkoxy,        halo-C₁₋₈alkoxy, amino, C₁₋₈alkyl-amino, (C₁₋₈alkyl)₂-amino or        C₁₋₈alkyl-thio;    -   R₆ is, in each instance, independently selected from halogen,        hydroxy, cyano, nitro, C₁₋₈alkyl, C₂₋₈alkenyl, halo-C₁₋₈alkyl,        hydroxy-C₁₋₈alkyl, C₁₋₈alkoxy, halo-C₁₋₈alkoxy,        C₁₋₈alkoxy-C₁₋₈alkyl, amino, C₁₋₈alkyl-amino, (C₁₋₈alkyl)₂-amino        or C₁₋₈alkyl-thio; and,    -   R₇ is C₃₋₁₄cycloalkyl, C₃₋₁₄cycloalkyl-oxy, aryl, heterocyclyl        or heteroaryl.

In one embodiment of the use of a compound of Formula (I), w₁ isC—R_(a).

In another embodiment of the use of a compound of Formula (I), w₁ is N.

In one embodiment of the use of a compound of Formula (I), w₂ isC—R_(b).

In another embodiment of the use of a compound of Formula (I), w₂ is N.

In one embodiment of the use of a compound of Formula (I), w₃ isC—R_(a).

In another embodiment of the use of a compound of Formula (I), w₃ is N.

In one embodiment of the use of a compound of Formula (I), w₄ isC—R_(a).

In another embodiment of the use of a compound of Formula (I), w₄ is N.

In one embodiment of the use of a compound of Formula (I), w₅ isC—R_(a).

In another embodiment of the use of a compound of Formula (I), w₅ is N.

In one embodiment of the use of a compound of Formula (I), w₆ isC—R_(c).

In another embodiment of the use of a compound of Formula (I), w₆ is N.

In one embodiment of the use of a compound of Formula (I), w₇ isC—R_(a).

In another embodiment of the use of a compound of Formula (I), w₇ is N.

In one embodiment of the use of a compound of Formula (I), w₃ is C—R₁and w₆ is C—R₂.

In another embodiment of the use of a compound of Formula (I), w₃ isC—R₂ and w₆ is C—R₁.

In one embodiment of the use of a compound of Formula (I), w₄ is C—R₁and w₇ is C—R₂.

In another embodiment of the use of a compound of Formula (I), w₄ isC—R₂ and w₇ is C—R₁.

In one embodiment of the use of a compound of Formula (I), w₃ is C—R₁,w₆ is C—R₂ and w₁, w₄, w₅ and w₇ are independently C—R_(a) or N and w₂is C—R_(b) or N.

In another embodiment of the use of a compound of Formula (I), w₃ isC—R₂, w₆ is C—R₁ and w₁, w₄, w₅ and w₇ are independently C—R_(a) or Nand w₂ is C—R_(b) or N.

In one embodiment of the use of a compound of Formula (I), w₄ is C—R₁,w₇ is C—R₂, w₁, w₃ and w₅ are independently C—R_(a) or N, w₂ is C—R_(b)or N and w₆ is C—R_(c) or N.

In another embodiment of the use of a compound of Formula (I), w₄ isC—R₂, w₇ is C—R₁, w₁, w₃ and w₅ are independently C—R_(a) or N, w₂ isC—R_(b) or N and w₆ is C—R_(c) or N.

In one embodiment of the use of a compound of Formula (I), w₁ and w₂ areN.

In one embodiment of the use of a compound of Formula (I), w₁ and w₃ areN.

In one embodiment of the use of a compound of Formula (I), w₁ and w₄ areN.

In one embodiment of the use of a compound of Formula (I), w₁ and w₅ areN.

In one embodiment of the use of a compound of Formula (I), w₁ and w₆ areN.

In one embodiment of the use of a compound of Formula (I), w₁ and w₇ areN.

In one embodiment of the use of a compound of Formula (I),

R₁ is C₁₋₈alkyl, amino, C₁₋₈alkyl-amino, (C₁₋₈alkyl)₂-amino,C₁₋₈alkoxy-C₁₋₈alkyl-amino, (C₁₋₈alkoxy-C₁₋₈alkyl)₂-amino,(C₁₋₈alkoxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino, amino-C₁₋₈alkyl,C₁₋₈alkyl-amino-C₁₋₈alkyl, (C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,C₁₋₈alkoxy-C₁₋₈alkyl-amino-C₁₋₈alkyl,(C₁₋₈alkoxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,(C₁₋₈alkoxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl, amino-C₁₋₈alkyl-amino,(amino-C₁₋₈alkyl)₂-amino, (amino-C₁₋₈alkyl)(C₁₋₈alkyl)amino,C₁₋₈alkyl-amino-C₁₋₈alkyl-amino, (C₁₋₈alkyl-amino-C₁₋₈alkyl)₂-amino,(C₁₋₈alkyl-amino-C₁₋₈alkyl)(C₁₋₈alkyl)amino,(C₁₋₈alkyl)₂-amino-C₁₋₈alkyl-amino,[(C₁₋₈alkyl)₂-amino-C₁₋₈alkyl](C₁₋₈alkyl)amino, amino-C₁₋₈alkoxy,C₁₋₈alkyl-amino-C₁₋₈alkoxy, (C₁₋₈alkyl)₂-amino-C₁₋₈alkoxy,C₁₋₈alkoxy-C-alkyl-amino-C₁₋₈alkoxy,(C₁₋₈alkoxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkoxy,(C₁₋₈alkoxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkoxy, amino-C₂₋₈alkenyl,C₁₋₈alkyl-amino-C₂₋₈alkenyl, (C₁₋₈alkyl)₂-amino-C₂₋₈alkenyl,amino-C₂₋₈alkynyl, C₁₋₈alkyl-amino-C₂₋₈alkynyl,(C₁₋₈alkyl)₂-amino-C₂₋₈alkynyl, halo-C₁₋₈alkyl-amino,(halo-C₁₋₈alkyl)₂-amino, (halo-C₁₋₈alkyl)(C₁₋₈alkyl)amino,hydroxy-C₁₋₈alkyl, hydroxy-C₁₋₈alkoxy-C₁₋₈alkyl,hydroxy-C₁₋₈alkyl-amino, (hydroxy-C₁₋₈alkyl)₂-amino,(hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino, hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkyl,(hydroxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,(hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl,hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkoxy,(hydroxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkoxy,(hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkoxy,hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkyl-amino,(hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkyl)₂-amino,(hydroxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl-amino,(hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkyl)(C₁₋₈alkyl)amino,(hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl-amino,[(hydroxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl](C₁₋₈alkyl)amino,[(hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl](C₁₋₈alkyl)amino,heterocyclyl, heterocyclyl-C₁₋₈alkyl, heterocyclyl-C₁₋₈alkoxy,heterocyclyl-amino, (heterocyclyl)(C₁₋₈alkyl)amino,heterocyclyl-amino-C₁₋₈alkyl, heterocyclyl-C₁₋₈alkyl-amino,(heterocyclyl-C₁₋₈alkyl)₂-amino,(heterocyclyl-C₁₋₈alkyl)(C₁₋₈alkyl)amino,heterocyclyl-C₁₋₈alkyl-amino-C₁₋₈alkyl,(heterocyclyl-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,(heterocyclyl-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl, heterocyclyl-oxy,heterocyclyl-carbonyl, heterocyclyl-carbonyl-oxy, C₃₋₁₄cycloalkyl,aryl-C₁₋₈alkyl-amino, (aryl-C₁₋₈alkyl)₂-amino,(aryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino, aryl-C₁₋₈alkyl-amino-C₁₋₈alkyl,(aryl-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,(aryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl, heteroaryl,heteroaryl-C₁₋₈alkyl, heteroaryl-C₁₋₈alkoxy, heteroaryl-amino,heteroaryl-C₁₋₈alkyl-amino, (heteroaryl-C₁₋₈alkyl)₂-amino,(heteroaryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino,heteroaryl-C₁₋₈alkyl-amino-C₁₋₈alkyl,(heteroaryl-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl or(heteroaryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl; wherein, each instanceof heterocyclyl, C₃₋₁₄cycloalkyl, aryl and heteroaryl is optionallysubstituted with R₃ and R₄ substituents.

In another embodiment of the use of a compound of Formula (I),

R₁ is amino, (C₁₋₈alkyl)₂-amino, C₁₋₈alkoxy-C₁₋₈alkyl-amino,(C₁₋₈alkoxy-C₁₋₈alkyl)₂-amino, amino-C₁₋₈alkyl,C₁₋₈alkyl-amino-C₁₋₈alkyl, (C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,C₁₋₈alkoxy-C₁₋₈alkyl-amino-C₁₋₈alkyl,(C₁₋₈alkoxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,(C₁₋₈alkoxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl, amino-C₁₋₈alkyl-amino,(amino-C₁₋₈alkyl)₂-amino, (amino-C₁₋₈alkyl)(C₁₋₈alkyl)amino,C₁₋₈alkyl-amino-C₁₋₈alkyl-amino, (C₁₋₈alkyl-amino-C₁₋₈alkyl)₂-amino,(C₁₋₈alkyl-amino-C₁₋₈alkyl)(C₁₋₈alkyl)amino,(C₁₋₈alkyl)₂-amino-C₁₋₈alkyl-amino,[(C₁₋₈alkyl)₂-amino-C₁₋₈alkyl](C₁₋₈alkyl)amino, amino-C₁₋₈alkoxy,C₁₋₈alkyl-amino-C₁₋₈alkoxy, (C₁₋₈alkyl)₂-amino-C₁₋₈alkoxy,C₁₋₈alkoxy-C₁₋₈alkyl-amino-C₁₋₈alkoxy,(C₁₋₈alkoxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkoxy,(C₁₋₈alkoxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkoxy, amino-C₂₋₈alkenyl,C₁₋₈alkyl-amino-C₂₋₈alkenyl, (C₁₋₈alkyl)₂-amino-C₂₋₈alkenyl,amino-C₂₋₈alkynyl, C₁₋₈alkyl-amino-C₂₋₈alkynyl,(C₁₋₈alkyl)₂-amino-C₂₋₈alkynyl, halo-C₁₋₈alkyl-amino,(halo-C₁₋₈alkyl)₂-amino, (halo-C₁₋₈alkyl)(C₁₋₈alkyl)amino,hydroxy-C₁₋₈alkyl, hydroxy-C₁₋₈alkoxy-C₁₋₈alkyl,hydroxy-C₁₋₈alkyl-amino, (hydroxy-C₁₋₈alkyl)₂-amino,(hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino, hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkyl,(hydroxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,(hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl,hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkoxy,(hydroxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkoxy,(hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkoxy,hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkyl-amino,(hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkyl)₂-amino,(hydroxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl-amino,(hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkyl)(C₁₋₈alkyl)amino,(hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl-amino,[(hydroxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl](C₁₋₈alkyl)amino,[(hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl](C₁₋₈alkyl)amino,heterocyclyl, heterocyclyl-C₁₋₈alkyl, heterocyclyl-C₁₋₈alkoxy,heterocyclyl-amino, (heterocyclyl)(C₁₋₈alkyl)amino,heterocyclyl-amino-C₁₋₈alkyl, heterocyclyl-C₁₋₈alkyl-amino,(heterocyclyl-C₁₋₈alkyl)₂-amino,(heterocyclyl-C₁₋₈alkyl)(C₁₋₈alkyl)amino,heterocyclyl-C₁₋₈alkyl-amino-C₁₋₈alkyl,(heterocyclyl-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,(heterocyclyl-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl, heterocyclyl-oxy,heterocyclyl-carbonyl, heterocyclyl-carbonyl-oxy, C₃₋₁₄cycloalkyl,aryl-C₁₋₈alkyl-amino, (aryl-C₁₋₈alkyl)₂-amino,(aryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino, aryl-C₁₋₈alkyl-amino-C₁₋₈alkyl,(aryl-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,(aryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl, heteroaryl,heteroaryl-C₁₋₈alkyl, heteroaryl-C₁₋₈alkoxy, heteroaryl-C₁₋₈alkyl-amino,(heteroaryl-C₁₋₈alkyl)₂-amino, (heteroaryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino,heteroaryl-C₁₋₈alkyl-amino-C₁₋₈alkyl,(heteroaryl-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl or(heteroaryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl; wherein, each instanceof heterocyclyl, C₃₋₁₄cycloalkyl, aryl and heteroaryl is optionallysubstituted with R₃ and R₄ substituents.

In another embodiment of the use of a compound of Formula (I),

R₁ is C₁₋₈alkyl, amino, C₁₋₈alkyl-amino, (C₁₋₈alkyl)₂-amino,C₁₋₈alkoxy-C₁₋₈alkyl-amino, (C₁₋₈alkoxy-C₁₋₈alkyl)₂-amino,(C₁₋₈alkoxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino, amino-C₁₋₈alkyl,C₁₋₈alkyl-amino-C₁₋₈alkyl, (C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,C₁₋₈alkoxy-C₁₋₈alkyl-amino-C₁₋₈alkyl,(C₁₋₈alkoxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,(C₁₋₈alkoxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl, amino-C₁₋₈alkyl-amino,(amino-C₁₋₈alkyl)₂-amino, (amino-C₁₋₈alkyl)(C₁₋₈alkyl)amino,C₁₋₈alkyl-amino-C₁₋₈alkyl-amino, (C₁₋₈alkyl-amino-C₁₋₈alkyl)₂-amino,(C₁₋₈alkyl-amino-C₁₋₈alkyl)(C₁₋₈alkyl)amino,(C₁₋₈alkyl)₂-amino-C₁₋₈alkyl-amino,[(C₁₋₈alkyl)₂-amino-C₁₋₈alkyl](C₁₋₈alkyl)amino, amino-C₁₋₈alkoxy,C₁₋₈alkyl-amino-C₁₋₈alkoxy, (C₁₋₈alkyl)₂-amino-C₁₋₈alkoxy,C₁₋₈alkoxy-C₁₋₈alkyl-amino-C₁₋₈alkoxy,(C₁₋₈alkoxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkoxy,(C₁₋₈alkoxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkoxy, amino-C₂₋₈alkenyl,C₁₋₈alkyl-amino-C₂₋₈alkenyl, (C₁₋₈alkyl)₂-amino-C₂₋₈alkenyl,amino-C₂₋₈alkynyl, C₁₋₈alkyl-amino-C₂₋₈alkynyl,(C₁₋₈alkyl)₂-amino-C₂₋₈alkynyl, halo-C₁₋₈alkyl-amino,(halo-C₁₋₈alkyl)₂-amino, (halo-C₁₋₈alkyl)(C₁₋₈alkyl)amino,hydroxy-C₁₋₈alkyl, hydroxy-C₁₋₈alkoxy-C₁₋₈alkyl,hydroxy-C₁₋₈alkyl-amino, (hydroxy-C₁₋₈alkyl)₂-amino,(hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino, hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkyl,(hydroxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,(hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl,hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkoxy,(hydroxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkoxy,(hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkoxy,hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkyl-amino,(hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkyl)₂-amino,(hydroxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl-amino,(hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkyl)(C₁₋₈alkyl)amino,(hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl-amino,[(hydroxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl](C₁₋₈alkyl)amino or[(hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl](C₁₋₈alkyl)amino.

In another embodiment of the use of a compound of Formula (I),

R₁ is heterocyclyl, heterocyclyl-C₁₋₈alkyl, heterocyclyl-C₁₋₈alkoxy,heterocyclyl-amino, (heterocyclyl)(C₁₋₈alkyl)amino,heterocyclyl-amino-C₁₋₈alkyl, heterocyclyl-C₁₋₈alkyl-amino,(heterocyclyl-C₁₋₈alkyl)₂-amino,(heterocyclyl-C₁₋₈alkyl)(C₁₋₈alkyl)amino,heterocyclyl-C₁₋₈alkyl-amino-C₁₋₈alkyl,(heterocyclyl-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,(heterocyclyl-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl, heterocyclyl-oxy,heterocyclyl-carbonyl, heterocyclyl-carbonyl-oxy, C₃₋₁₄cycloalkyl,aryl-C₁₋₈alkyl-amino, (aryl-C₁₋₈alkyl)₂-amino,(aryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino, aryl-C₁₋₈alkyl-amino-C₁₋₈alkyl,(aryl-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,(aryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl, heteroaryl,heteroaryl-C₁₋₈alkyl, heteroaryl-C₁₋₈alkoxy, heteroaryl-amino,heteroaryl-C₁₋₈alkyl-amino, (heteroaryl-C₁₋₈alkyl)₂-amino,(heteroaryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino,heteroaryl-C₁₋₈alkyl-amino-C₁₋₈alkyl,(heteroaryl-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl or(heteroaryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl; wherein, each instanceof heterocyclyl, C₃₋₁₄cycloalkyl, aryl and heteroaryl is optionallysubstituted with R₃ and R₄ substituents.

In another embodiment of the use of a compound of Formula (I),

R₁ is heterocyclyl, heterocyclyl-C₁₋₈alkyl, heterocyclyl-C₁₋₈alkoxy,heterocyclyl-amino, (heterocyclyl)(C₁₋₈alkyl)amino,heterocyclyl-amino-C₁₋₈alkyl, heterocyclyl-C₁₋₈alkyl-amino,(heterocyclyl-C₁₋₈alkyl)₂-amino,(heterocyclyl-C₁₋₈alkyl)(C₁₋₈alkyl)amino,heterocyclyl-C₁₋₈alkyl-amino-C₁₋₈alkyl,(heterocyclyl-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,(heterocyclyl-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl, heterocyclyl-oxy,heterocyclyl-carbonyl or heterocyclyl-carbonyl-oxy; wherein, eachinstance of heterocyclyl is optionally substituted with R₃ and R₄substituents.

In another embodiment of the use of a compound of Formula (I), R₁ isheterocyclyl optionally substituted with R₃ and R₄ substituents.

In another embodiment of the use of a compound of Formula (I), R₁ isC₃₋₁₄cycloalkyl optionally substituted with R₃ and R₄ substituents.

In another embodiment of the use of a compound of Formula (I),

R₁ is aryl-C₁₋₈alkyl-amino, (aryl-C₁₋₈alkyl)₂-amino,(aryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino, aryl-C₁₋₈alkyl-amino-C₁₋₈alkyl,(aryl-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl or(aryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl; wherein, each instance ofaryl is optionally substituted with R₃ and R₄ substituents.

In another embodiment of the use of a compound of Formula (I), R₁ isaryl-C₁₋₈alkyl-amino optionally substituted with R₃ and R₄ substituents.

In another embodiment of the use of a compound of Formula (I),

R₁ is heteroaryl, heteroaryl-C₁₋₈alkyl, heteroaryl-C₁₋₈alkoxy,heteroaryl-amino, heteroaryl-C₁₋₈alkyl-amino,(heteroaryl-C₁₋₈alkyl)₂-amino, (heteroaryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino,heteroaryl-C₁₋₈alkyl-amino-C₁₋₈alkyl,(heteroaryl-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl or(heteroaryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl; wherein, each instanceof heterocyclyl, C₃₋₁₄cycloalkyl, aryl and heteroaryl is optionallysubstituted with R₃ and R₄ substituents.

In another embodiment of the use of a compound of Formula (I), R₁ isheteroaryl optionally substituted with R₃ and R₄ substituents.

In one embodiment of the use of a compound of Formula (I),

R₁ is heterocyclyl selected from azetidinyl, tetrahydrofuranyl,pyrrolidinyl, piperidinyl, piperazinyl, 1,4-diazepanyl,1,2,5,6-tetrahydropyridinyl, 1,2,3,6-tetrahydropyridinyl,hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl,(3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl,(3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl,hexahydropyrrolo[3,4-b]pyrrol-(2H)-yl,(3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-(2H)-yl,hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl,(3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl,octahydro-5H-pyrrolo[3,2-c]pyridinyl,octahydro-6H-pyrrolo[3,4-b]pyridinyl,(4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridinyl,(4aS,7aS)-octahydro-6H-pyrrolo[3,4-b]pyridinyl,hexahydropyrrolo[1,2-a]pyrazin-(2H)-one,hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl,(7R,8aS)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl,(8aS)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl,(8aR)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl,(8aS)-octahydropyrrolo[1,2-a]pyrazin-(1H)-yl,(8aR)-octahydropyrrolo[1,2-a]pyrazin-(1H)-yl,octahydro-2H-pyrido[1,2-a]pyrazinyl, 3-azabicyclo[3.1.0]hexyl,(1R,5S)-3-azabicyclo[3.1.0]hexyl, 8-azabicyclo[3.2.1]octyl,(1R,5S)-8-azabicyclo[3.2.1]octyl, 8-azabicyclo[3.2.1]oct-2-enyl,(1R,5S)-8-azabicyclo[3.2.1]oct-2-enyl, 9-azabicyclo[3.3.1]nonyl,(1R,5S)-9-azabicyclo[3.3.1]nonyl, 2,5-diazabicyclo[2.2.1]heptyl,(1S,4S)-2,5-diazabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.2]octyl,3,8-diazabicyclo[3.2.1]octyl, (1R,5S)-3,8-diazabicyclo[3.2.1]octyl,1,4-diazabicyclo[3.2.2]nonyl, azaspiro[3.3]heptyl,2,6-diazaspiro[3.3]heptyl, 2,7-diazaspiro[3.5]nonyl,5,8-diazaspiro[3.5]nonyl, 2,7-diazaspiro[4.4]nonyl or6,9-diazaspiro[4.5]decyl; wherein, each instance of heterocyclyl isoptionally substituted with R₃ and R₄ substituents.

In another embodiment of the use of a compound of Formula (I),

R₁ is heterocyclyl selected from azetidin-1-yl, tetrahydrofuran-3-yl,pyrrolidin-1-yl, piperidin-1-yl, piperidin-4-yl, piperazin-1-yl,1,4-diazepan-1-yl, 1,2,5,6-tetrahydropyridin-5-yl,1,2,3,6-tetrahydropyridin-4-yl, hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl,(3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl,(3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl,(3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl,hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl,(3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl,octahydro-5H-pyrrolo[3,2-c]pyridin-5-yl,octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl,(4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl,(4aS,7aS)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl,hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one,hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl,(7R,8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl,(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl,(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl,(8aS)-octahydropyrrolo[1,2-a]pyrazin-2(1H)-yl,(8aR)-octahydropyrrolo[1,2-a]pyrazin-2(1H)-yl,octahydro-2H-pyrido[1,2-a]pyrazin-2-yl, 3-azabicyclo[3.1.0]hex-3-yl,8-azabicyclo[3.2.1]oct-3-yl, (1R,5S)-8-azabicyclo[3.2.1]oct-3-yl,8-azabicyclo[3.2.1]oct-2-en-3-yl,(1R,5S)-8-azabicyclo[3.2.1]oct-2-en-3-yl, 9-azabicyclo[3.3.1]non-3-yl,(1R,5S)-9-azabicyclo[3.3.1]non-3-yl, 2,5-diazabicyclo[2.2.1]hept-2-yl,(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl,2,5-diazabicyclo[2.2.2]oct-2-yl, 3,8-diazabicyclo[3.2.1]oct-3-yl,(1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl,1,4-diazabicyclo[3.2.2]non-4-yl, azaspiro[3.3]hept-2-yl,2,6-diazaspiro[3.3]hept-2-yl, 2,7-diazaspiro[3.5]non-7-yl,5,8-diazaspiro[3.5]non-8-yl, 2,7-diazaspiro[4.4]non-2-yl or6,9-diazaspiro[4.5]dec-9-yl; wherein, each instance of heterocyclyl isoptionally substituted with R₃ and R₄ substituents.

In another embodiment of the use of a compound of Formula (I),

R₁ is substituted heterocyclyl selected from 4-methyl-1,4-diazepan-1-yl,(3aS,6aS)-1-methylhexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl,(3aS,6aS)-5-methylhexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl,(3aR,6aR)-1-methylhexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl,(3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl,(3aR,6aS)-5-(2-hydroxyethyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl,(3aR,6aS)-5-(propan-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl,(3aR,6aS)-5-ethylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl,(4aR,7aR)-1-methyloctahydro-6H-pyrrolo[3,4-b]pyridin-6-yl,(4aR,7aR)-1-ethyloctahydro-6H-pyrrolo[3,4-b]pyridin-6-yl,(4aR,7aR)-1-(2-hydroxyethyl)octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl,(4aS,7aS)-1-methyloctahydro-6H-pyrrolo[3,4-b]pyridin-6-yl,(4aS,7aS)-1-(2-hydroxyethyl)octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl,(7R,8aS)-7-hydroxyhexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl,(8aS)-8a-methyloctahydropyrrolo[1,2-a]pyrazin-2(1H)-yl,(8aR)-8a-methyloctahydropyrrolo[1,2-a]pyrazin-2(1H)-yl,(1R,5S,6s)-6-(dimethylamino)-3-azabicyclo[3.1.0]hex-3-yl,(1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl,9-methyl-9-azabicyclo[3.3.1]non-3-yl,(3-exo)-9-methyl-9-azabicyclo[3.3.1]non-3-yl,(1R,5S)-9-methyl-9-azabicyclo[3.3.1]non-3-yl,(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl or(1S,4S)-5-ethyl-2,5-diazabicyclo[2.2.1]hept-2-yl.

In one embodiment of the use of a compound of Formula (I), R₁ isheterocyclyl-C₁₋₈alkyl, wherein heterocyclyl is selected frommorpholinyl, piperidinyl, piperazinyl, imidazolyl or pyrrolidinyl; and,wherein, each instance of heterocyclyl is optionally substituted with R₃and R₄ substituents.

In another embodiment of the use of a compound of Formula (I), R₁ isheterocyclyl-C₁₋₈alkyl selected from morpholin-4-yl-methyl,morpholin-4-yl-ethyl, morpholin-4-yl-propyl, piperidin-1-yl-methyl,piperazin-1-yl-methyl, piperazin-1-yl-ethyl, piperazin-1-yl-propyl,piperazin-1-yl-butyl, imidazol-1-yl-methyl, imidazol-1-yl-ethyl,imidazol-1-yl-propyl, imidazol-1-yl-butyl, pyrrolidin-1-yl-methyl,pyrrolidin-1-yl-ethyl, pyrrolidin-1-yl-propyl or pyrrolidin-1-yl-butyl;wherein, each instance of heterocyclyl is optionally substituted with R₃and R₄ substituents.

In one embodiment of the use of a compound of Formula (I), R₁ isheterocyclyl-C₁₋₈alkoxy, wherein heterocyclyl is selected frompyrrolidinyl, piperidinyl or morpholinyl; and, wherein, each instance ofheterocyclyl is optionally substituted with R₃ and R₄ substituents.

In another embodiment of the use of a compound of Formula (I), R₁ isheterocyclyl-C₁₋₈alkoxy selected from pyrrolidin-2-yl-methoxy,pyrrolidin-2-yl-ethoxy, pyrrolidin-1-yl-methoxy, pyrrolidin-1-yl-ethoxy,piperidin-1-yl-methoxy, piperidin-1-yl-ethoxy, morpholin-4-yl-methoxy ormorpholin-4-yl-ethoxy; wherein, each instance of heterocyclyl isoptionally substituted with R₃ and R₄ substituents.

In one embodiment of the use of a compound of Formula (I), R₁ isheterocyclyl-amino, wherein heterocyclyl is selected from azetidinyl,pyrrolidinyl, piperidinyl, 9-azabicyclo[3.3.1]nonyl or(1R,5S)-9-azabicyclo[3.3.1]nonyl; and, wherein, each instance ofheterocyclyl is optionally substituted with R₃ and R₄ substituents.

In another embodiment of the use of a compound of Formula (I), R₁ isheterocyclyl-amino selected from azetidin-3-yl-amino,pyrrolidin-3-yl-amino, piperidin-4-yl-amino,9-azabicyclo[3.3.1]non-3-yl-amino,(1R,5S)-9-azabicyclo[3.3.1]non-3-yl-amino,9-methyl-9-azabicyclo[3.3.1]non-3-yl-amino,(3-exo)-9-methyl-9-azabicyclo[3.3.1]non-3-yl-amino or(1R,5S)-9-methyl-9-azabicyclo[3.3.1]non-3-yl-amino; wherein, eachinstance of heterocyclyl is optionally substituted with R₃ and R₄substituents.

In one embodiment of the use of a compound of Formula (I), R₁ is(heterocyclyl)(C₁₋₈alkyl)amino, wherein heterocyclyl is selected frompyrrolidinyl or piperidinyl; and, wherein, each instance of heterocyclylis optionally substituted with R₃ and R₄ substituents.

In another embodiment of the use of a compound of Formula (I), R₁ is(heterocyclyl)(C₁₋₈alkyl)amino selected from(pyrrolidin-3-yl)(methyl)amino or (piperidin-4-yl)(methyl)amino;wherein, each instance of heterocyclyl is optionally substituted with R₃and R₄ substituents.

In one embodiment of the use of a compound of Formula (I), R₁ isheterocyclyl-amino-C₁₋₈alkyl, wherein heterocyclyl is selected fromtetrahydrofuranyl; and, wherein, each instance of heterocyclyl isoptionally substituted with R₃ and R₄ substituents.

In another embodiment of the use of a compound of Formula (I), R₁ isheterocyclyl-amino-C₁₋₈alkyl, selected from3-(tetrahydrofuran-3-yl-amino)propyl; wherein, each instance ofheterocyclyl is optionally substituted with R₃ and R₄ substituents.

In one embodiment of the use of a compound of Formula (I), R₁ isheterocyclyl-C₁₋₈alkyl-amino-C₁₋₈alkyl, wherein heterocyclyl is selectedfrom tetrahydrofuranyl, thienyl or pyridinyl; and, wherein, eachinstance of heterocyclyl is optionally substituted with R₃ and R₄substituents.

In another embodiment of the use of a compound of Formula (I), R₁ isheterocyclyl-C₁₋₈alkyl-amino-C₁₋₈alkyl, selected from3-[(tetrahydrofuran-2-ylmethyl)amino]propyl,3-[(thienyl-3-ylmethyl)amino]propyl, 3-[(pyridin-2-ylmethyl)amino]propylor 3-[(pyridin-4-ylmethyl)amino]propyl; wherein, each instance ofheterocyclyl is optionally substituted with R₃ and R₄ substituents.

In one embodiment of the use of a compound of Formula (I), R₁ isheterocyclyl-oxy, wherein heterocyclyl is selected from pyrrolidinyl orpiperidinyl; and, wherein, each instance of heterocyclyl is optionallysubstituted with R₃ and R₄ substituents.

In another embodiment of the use of a compound of Formula (I), R₁ isheterocyclyl-oxy selected from pyrrolidin-3-yl-oxy orpiperidin-4-yl-oxy; wherein, each instance of heterocyclyl is optionallysubstituted with R₃ and R₄ substituents.

In one embodiment of the use of a compound of Formula (I), R₁ isheterocyclyl-carbonyl, wherein heterocyclyl is selected frompiperazinyl; and, wherein, each instance of heterocyclyl is optionallysubstituted with R₃ and R₄ substituents.

In another embodiment of the use of a compound of Formula (I), R₁ isheterocyclyl-carbonyl selected from piperazin-1-yl-carbonyl; wherein,each instance of heterocyclyl is optionally substituted with R₃ and R₄substituents.

In one embodiment of the use of a compound of Formula (I), R₁ isheterocyclyl-carbonyl-oxy, wherein heterocyclyl is selected frompiperazinyl; and, wherein, each instance of heterocyclyl is optionallysubstituted with R₃ and R₄ substituents.

In another embodiment of the use of a compound of Formula (I), R₁ isheterocyclyl-carbonyl-oxy selected from piperazin-1-yl-carbonyl-oxy;wherein, each instance of heterocyclyl is optionally substituted with R₃and R₄ substituents.

In one embodiment of the use of a compound of Formula (I), R₁ isC₃₋₁₄cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cyclohexenyl or cycloheptyl; wherein, each instance ofC₃₋₁₄cycloalkyl is optionally substituted with R₃ and R₄ substituents.

In another embodiment of the use of a compound of Formula (I), R₁ isC₃₋₈cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cyclohexenyl or cycloheptyl; wherein, each instance ofC₃₋₈cycloalkyl is optionally substituted with R₃ and R₄ substituents.

In one embodiment of the use of a compound of Formula (I), R₁ isaryl-C₁₋₈alkyl-amino-C₁₋₈alkyl, wherein aryl is selected from phenyl;and, wherein, each instance of aryl is optionally substituted with R₃and R₄ substituents.

In another embodiment of the use of a compound of Formula (I), R₁ isaryl-C₁₋₈alkyl-amino-C₁₋₈alkyl selected from 3-(benzylamino)propyl;wherein, each instance of aryl is optionally substituted with R₃ and R₄substituents.

In one embodiment of the use of a compound of Formula (I), R₁ isheteroaryl, wherein heteroaryl is selected from pyridinyl; and, wherein,each instance of heteroaryl is optionally substituted with R₃ and R₄substituents.

In another embodiment of the use of a compound of Formula (I), R₁ isheteroaryl selected from pyridin-4-yl; wherein, each instance ofheteroaryl is optionally substituted with R₃ and R₄ substituents.

In one embodiment of the use of a compound of Formula (I), R₁ isheteroaryl-C₁₋₈alkyl, wherein heteroaryl is selected from 1H-imidazolyl;and, wherein, each instance of heteroaryl is optionally substituted withR₃ and R₄ substituents.

In another embodiment of the use of a compound of Formula (I), R₁ isheteroaryl-C₁₋₈alkyl selected from 1H-imidazol-1-yl-methyl; wherein,each instance of heteroaryl is optionally substituted with R₃ and R₄substituents.

In one embodiment of the use of a compound of Formula (I), R₁ is(heteroaryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino, wherein heteroaryl is selectedfrom pyridinyl; and, wherein, each instance of heteroaryl is optionallysubstituted with R₃ and R₄ substituents.

In another embodiment of the use of a compound of Formula (I), R₁ is(heteroaryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino selected from(pyridin-3-ylmethyl)(methyl)amino; wherein, each instance of heteroarylis optionally substituted with R₃ and R₄ substituents.

In one embodiment of the use of a compound of Formula (I), R₁ isheteroaryl-C₁₋₈alkyl-amino-C₁₋₈alkyl, wherein heteroaryl is selectedfrom thienyl or pyridinyl; and, wherein, each instance of heteroaryl isoptionally substituted with R₃ and R₄ substituents.

In another embodiment of the use of a compound of Formula (I), R₁ isheteroaryl-C₁₋₈alkyl-amino-C₁₋₈alkyl selected fromthien-3-yl-methyl-amino-propyl, pyridin-2-yl-methyl-amino-propyl,pyridin-3-yl-methyl-amino-propyl or pyridin-4-yl-methyl-amino-propyl;wherein, each instance of heteroaryl is optionally substituted with R₃and R₄ substituents.

In one embodiment of the use of a compound of Formula (I), R₃ isselected from cyano, halogen, hydroxy, oxo, C₁₋₈alkyl, halo-C₁₋₈alkyl,C₁₋₈alkyl-carbonyl, C₁₋₈alkoxy, halo-C₁₋₈alkoxy, C₁₋₈alkoxy-C₁₋₈alkyl,C₁₋₈alkoxy-carbonyl, amino, C₁₋₈alkyl-amino, (C₁₋₈alkyl)₂-amino,amino-C₁₋₈alkyl, C₁₋₈alkyl-amino-C₁₋₈alkyl,(C₁₋₈alkyl)₂-amino-C₁₋₈alkyl, amino-C₁₋₈alkyl-amino,C₁₋₈alkyl-amino-C₁₋₈alkyl-amino, (C₁₋₈alkyl)₂-amino-C₁₋₈alkyl-amino,C₁₋₈alkoxy-C₁₋₈alkyl-amino, C₁₋₈alkyl-carbonyl-amino,C₁₋₈alkoxy-carbonyl-amino, hydroxy-C₁₋₈alkyl,hydroxy-C₁₋₈alkoxy-C₁₋₈alkyl, hydroxy-C₁₋₈alkyl-amino,(hydroxy-C₁₋₈alkyl)₂-amino or (hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino.

In another embodiment of the use of a compound of Formula (I), R₃ isselected from cyano, halogen, hydroxy, oxo, C₁₋₈alkyl, halo-C₁₋₈alkyl,C₁₋₈alkoxy, C₁₋₈alkoxy-C₁₋₈alkyl, C₁₋₈alkoxy-carbonyl, amino,C₁₋₈alkyl-amino, (C₁₋₈alkyl)₂-amino, amino-C₁₋₈alkyl,C₁₋₈alkyl-amino-C₁₋₈alkyl, (C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,C₁₋₈alkyl-amino-C₁₋₈alkyl-amino, C₁₋₈alkoxy-C₁₋₈alkyl-amino,C₁₋₈alkoxy-carbonyl-amino, hydroxy-C₁₋₈alkyl,hydroxy-C₁₋₈alkoxy-C₁₋₈alkyl, hydroxy-C₁₋₈alkyl-amino,(hydroxy-C₁₋₈alkyl)₂-amino or (hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino.

In one embodiment of the use of a compound of Formula (I), R₃ isC₁₋₈alkyl selected from methyl, ethyl, propyl, isopropyl or tert-butyl.

In another embodiment of the use of a compound of Formula (I), R₃ isC₁₋₈alkyl selected from ethyl, propyl, isopropyl or tert-butyl.

In one embodiment of the use of a compound of Formula (I), R₃ ishalo-C₁₋₈alkyl selected from trihalo-methyl, dihalo-methyl, halo-methyl,trihalo-ethyl, dihalo-ethyl, halo-ethyl, trihalo-propyl, dihalo-propylor halo-propyl; wherein, halo is selected from fluoro, chloro, bromo oriodo.

In another embodiment of the use of a compound of Formula (I), R₃ ishalo-C₁₋₈alkyl selected from trihalo-methyl, dihalo-methyl, halo-methyl,trihalo-ethyl, dihalo-ethyl, trihalo-propyl or dihalo-propyl; wherein,halo is selected from fluoro, chloro, bromo or iodo.

In one embodiment of the use of a compound of Formula (I), R₃ ishydroxy-C₁₋₈alkyl selected from hydroxy-methyl, hydroxy-ethyl,hydroxy-propyl, dihydroxy-propyl, hydroxy-butyl or dihydroxy-butyl.

In another embodiment of the use of a compound of Formula (I), R₃ ishydroxy-C₁₋₈alkyl selected from hydroxy-methyl, dihydroxy-propyl,hydroxy-butyl or dihydroxy-butyl.

In one embodiment of the use of compound of Formula (I), R₃ isC₁₋₈alkoxy selected from methoxy, ethoxy, propoxy or isopropoxy.

In one embodiment of the use of a compound of Formula (I), R₃ ishalo-C₁₋₈alkoxy selected from trihalo-methoxy, dihalo-methoxy,halo-methoxy, trihalo-ethoxy, dihalo-ethoxy, halo-ethoxy,trihalo-propoxy, dihalo-propoxy or halo-propoxy; wherein, halo isselected from fluoro, chloro, bromo or iodo.

In one embodiment of the use of a compound of Formula (I), R₃ isC₁₋₈alkoxy-carbonyl-amino selected from methoxy-carbonyl-amino,ethoxy-carbonyl-amino, propoxy-carbonyl-amino,isopropoxy-carbonyl-amino, tert-butoxy-carbonyl-amino.

In one embodiment of the use of a compound of Formula (I), R_(a) is, ineach instance, independently selected from hydrogen, halogen, C₁₋₈alkyl.

In one embodiment of the use of a compound of Formula (I), R_(a) is, ineach instance, optionally and independently deuterium.

In one embodiment of the use of a compound of Formula (I), R_(b) ishydrogen, halogen, C₁₋₈alkyl, C₁₋₈alkoxy.

In one embodiment of the use of a compound of Formula (I), R_(c) is, ineach instance, independently selected from hydrogen, halogen, C₁₋₈alkyl.

In one embodiment of the use of a compound of Formula (I), R_(c) is, ineach instance, optionally and independently deuterium.

In one embodiment of the use of a compound of Formula (I), R_(b) isdeuterium.

In one embodiment of the use of a compound of Formula (I), R₄ isC₃₋₁₄cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl or cycloheptyl; wherein, each instance of C₃₋₁₄cycloalkyl isoptionally substituted with R₅ substituents.

In another embodiment of the use of a compound of Formula (I), R₄ isC₃₋₈cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl or cycloheptyl; wherein, each instance of C₃₋₈cycloalkyl isoptionally substituted with R₅ substituents.

In one embodiment of the use of a compound of Formula (I), R₄ isC₃₋₁₄cycloalkyl-C₁₋₈alkyl, wherein C₃₋₁₄cycloalkyl is selected fromcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; and,wherein, each instance of C₃₋₁₄cycloalkyl is optionally substituted withR₅ substituents.

In another embodiment of the use of a compound of Formula (I), R₄ isC₃₋₁₄cycloalkyl-C₁₋₈alkyl, wherein C₃₋₈cycloalkyl is selected fromcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; and,wherein, each instance of C₃₋₈cycloalkyl is optionally substituted withR₅ substituents.

In one embodiment of the use of a compound of Formula (I), R₄ isC₃₋₁₄cycloalkyl-amino, wherein C₃₋₁₄cycloalkyl is selected fromcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; and,wherein, each instance of C₃₋₁₄cycloalkyl is optionally substituted withR₅ substituents.

In another embodiment of the use of a compound of Formula (I), R₄ isC₃₋₈cycloalkyl-amino, wherein C₃₋₈cycloalkyl is selected fromcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; and,wherein, each instance of C₃₋₈cycloalkyl is optionally substituted withR₅ substituents.

In one embodiment of the use of a compound of Formula (I), R₄ isaryl-C₁₋₈alkyl, aryl-C₁₋₈alkoxy-carbonyl or aryl-sulfonyloxy-C₁₋₈alkyl,wherein aryl is selected from phenyl; and, wherein, each instance ofaryl is optionally substituted with R₅ substituents.

In another embodiment of the use of a compound of Formula (I), R₄ isaryl-C₁₋₈alkyl or aryl-C₁₋₈alkoxy-carbonyl, wherein each instance ofaryl is optionally substituted with R₅ substituents.

In one embodiment of the use of a compound of Formula (I), R₄ isheterocyclyl selected from oxetanyl, pyrrolidinyl, piperidinyl,piperazinyl, 1,3-dioxanyl or morpholinyl, wherein each instance ofheterocyclyl is optionally substituted with R₅ substituents.

In another embodiment of the use of a compound of Formula (I), R₄ isheterocyclyl selected from oxetan-3-yl, pyrrolidin-1-yl, piperidin-1-yl,piperazin-1-yl, 1,3-dioxan-5-yl or morpholin-4-yl, wherein each instanceof heterocyclyl is optionally substituted with R₅ substituents.

In one embodiment of the use of a compound of Formula (I), R₄ isheterocyclyl-C₁₋₈alkyl, wherein each instance of heterocyclyl isselected from pyrrolidinyl or piperidinyl; and, wherein, each instanceof heterocyclyl is optionally substituted with R₅ substituents.

In another embodiment of the use of a compound of Formula (I), R₄ isheterocyclyl-C₁₋₈alkyl selected from pyrrolidin-1-yl-C₁₋₈alkyl orpiperidin-1-yl-C₁₋₈alkyl, wherein each instance of heterocyclyl isoptionally substituted with R₅ substituents.

In one embodiment of the use of a compound of Formula (I), R₅ isselected from halogen, hydroxy, cyano, nitro, halo-C₁₋₈alkyl,C₁₋₈alkoxy, halo-C₁₋₈alkoxy, amino, C₁₋₈alkyl-amino, (C₁₋₈alkyl)₂-aminoor C₁₋₈alkyl-thio; wherein, halogen and halo is selected from fluoro,chloro, bromo or iodo.

In one embodiment of the use of a compound of Formula (I), R₅ ishydroxy.

In one embodiment of the use of a compound of Formula (I), R₅ isC₁₋₈alkyl selected from methyl, ethyl, propyl, isopropyl, n-butyl ortert-butyl.

In another embodiment of the use of a compound of Formula (I), R₅ isC₁₋₈alkyl selected from ethyl, propyl, isopropyl or tert-butyl.

In one embodiment of the use of a compound of Formula (I), R₅ ishalo-C₁₋₈alkyl selected from trihalo-methyl, dihalo-methyl, halo-methyl,trihalo-ethyl, dihalo-ethyl, halo-ethyl, trihalo-propyl, dihalo-propylor halo-propyl; wherein, halo is selected from fluoro, chloro, bromo oriodo.

In one embodiment of the use of a compound of Formula (I), R₅ isC₁₋₈alkoxy selected from methoxy, ethoxy, propoxy or isopropoxy.

In one embodiment of the use of a compound of Formula (I), R₅ ishalo-C₁₋₈alkoxy selected from trihalo-methoxy, dihalo-methoxy,halo-methoxy, trihalo-ethoxy, dihalo-ethoxy, halo-ethoxy,trihalo-propoxy, dihalo-propoxy or halo-propoxy; wherein, halo isselected from fluoro, chloro, bromo or iodo.

In one embodiment of the use of a compound of Formula (I), R₂ is arylselected from phenyl optionally substituted with R₆ and R₇ substituents.

In one embodiment of the use of a compound of Formula (I), R₂ isaryl-amino, wherein aryl is selected from phenyl; and, wherein, eachinstance of aryl is optionally substituted with R₆ and R₇ substituents.

In another embodiment of the use of a compound of Formula (I), R₂ isaryl-amino selected from phenyl-amino; wherein, each instance of aryl isoptionally substituted with R₆ and R₇ substituents.

In one embodiment of the use of a compound of Formula (I), R₂ isaryl-amino-carbonyl, wherein aryl is selected from phenyl; and, wherein,each instance of aryl is optionally substituted with R₆ and R₇substituents.

In another embodiment of the use of a compound of Formula (I), R₂ isaryl-amino-carbonyl selected from phenyl-amino-carbonyl; wherein, eachinstance of aryl is optionally substituted with R₆ and R₇ substituents.

In one embodiment of the use of a compound of Formula (I),

R₂ is heterocyclyl selected from 1,2,3,6-tetrahydropyridinyl,1,3-benzodioxolyl or 2,3-dihydro-1,4-benzodioxinyl; wherein, eachinstance of heterocyclyl is optionally substituted with R₆ and R₇substituents.

In another embodiment of the use of a compound of Formula (I),

R₂ is heterocyclyl selected from 1,2,3,6-tetrahydropyridin-4-yl,1,3-benzodioxol-5-yl or 2,3-dihydro-1,4-benzodioxin-6-yl; wherein, eachinstance of heterocyclyl is optionally substituted with R₆ and R₇substituents.

In one embodiment of the use of a compound of Formula (I),

R₂ is heteroaryl selected from thienyl, 1H-pyrazolyl, 1H-imidazolyl,1,3-thiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, pyridinyl,pyrimidinyl, 1H-indolyl, 2H-indolyl, 1H-indazolyl, 2H-indazolyl,indolizinyl, benzofuranyl, benzothienyl, 1H-benzimidazolyl,1,3-benzothiazolyl, 1,3-benzoxazolyl, 9H-purinyl, furo[3,2-b]pyridinyl,furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl, thieno[3,2-c]pyridinyl,thieno[2,3-d]pyrimidinyl, 1H-pyrrolo[2,3-b]pyridinyl,1H-pyrrolo[2,3-c]pyridinyl, pyrrolo[1,2-a]pyrimidinyl,pyrrolo[1,2-a]pyrazinyl, pyrrolo[1,2-b]pyridazinyl,pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrazinyl,imidazo[1,2-a]pyridinyl, imidazo[1,2-a]pyrimidinyl,imidazo[1,2-c]pyrimidinyl, imidazo[1,2-b]pyridazinyl,imidazo[1,2-a]pyrazinyl, imidazo[2,1-b][1,3]thiazolyl,imidazo[2,1-b][1,3,4]thiadiazolyl, [1,3]oxazolo[4,5-b]pyridinyl orquinoxalinyl; wherein, each instance of heteroaryl is optionallysubstituted with R₆ and R₇ substituents.

In another embodiment of the use of a compound of Formula (I),

R₂ is heteroaryl selected from thien-2-yl, thien-3-yl, 1H-pyrazol-3-yl,1H-pyrazol-4-yl, 1H-pyrazol-5-yl, 1H-imidazol-1-yl, 1H-imidazol-4-yl,1,3-thiazol-2-yl, 1,2,4-oxadiazol-3-yl, 1,3,4-oxadiazol-2-yl,pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-4-yl, 1H-indol-3-yl,1H-indol-4-yl, 1H-indol-5-yl, 1H-indol-6-yl, 1H-indazol-5-yl,2H-indazol-5-yl, indolizin-2-yl, benzofuran-2-yl, benzofuran-5-yl,benzothien-2-yl, benzothien-3-yl, 1H-benzimidazol-2-yl,1H-benzimidazol-6-yl, 1,3-benzoxazol-2-yl, 1,3-benzoxazol-5-yl,1,3-benzoxazol-6-yl, 1,3-benzothiazol-2-yl, 1,3-benzothiazol-5-yl,1,3-benzothiazol-6-yl, 9H-purin-8-yl, furo[3,2-b]pyridin-2-yl,furo[3,2-c]pyridin-2-yl, furo[2,3-c]pyridin-2-yl,thieno[3,2-c]pyridin-2-yl, thieno[2,3-d]pyrimidin-6-yl,1H-pyrrolo[2,3-b]pyridin-5-yl, 1H-pyrrolo[2,3-c]pyridin-4-yl,pyrrolo[1,2-a]pyrimidin-7-yl, pyrrolo[1,2-a]pyrazin-7-yl,pyrrolo[1,2-b]pyridazin-2-yl, pyrazolo[1,5-a]pyridin-2-yl,pyrazolo[1,5-a]pyrazin-2-yl, imidazo[1,2-a]pyridin-2-yl,imidazo[1,2-a]pyridin-6-yl, imidazo[1,2-a]pyrimidin-2-yl,imidazo[1,2-a]pyrimidin-6-yl, imidazo[1,2-c]pyrimidin-2-yl,imidazo[1,2-b]pyridazin-2-yl, imidazo[1,2-a]pyrazin-2-yl,imidazo[2,1-b][1,3]thiazol-6-yl, imidazo[2,1-b][1,3,4]thiadiazol-6-yl,[1,3]oxazolo[4,5-b]pyridin-2-yl or quinoxalin-2-yl; wherein, eachinstance of heteroaryl is optionally substituted with R₆ and R₇substituents.

In another embodiment of the use of a compound of Formula (I),

R₂ is substituted heteroaryl selected from 4-methylthien-2-yl,1-methyl-1H-pyrazol-3-yl, 4-methyl-1H-pyrazol-3-yl,1-phenyl-1H-pyrazol-3-yl, 1-phenyl-1H-imidazol-4-yl,2-methyl-1-(pyridin-2-yl)-1H-imidazol-4-yl, 4-methyl-1,3-thiazol-2-yl,4-(trifluoromethyl)-1,3-thiazol-2-yl, 4-phenyl-1,3-thiazol-2-yl,5-phenyl-1,2,4-oxadiazol-3-yl, 3-fluoropyridin-4-yl,6-fluoropyridin-2-yl, 2-chloropyridin-4-yl, 4-chloropyridin-3-yl,5-chloropyridin-2-yl, 6-methylpyridin-3-yl,2-(trifluoromethyl)pyridin-3-yl, 4-(trifluoromethyl)pyridin-2-yl,6-(trifluoromethyl)pyridin-2-yl, 2-methoxypyridin-4-yl,4-methoxypyridin-3-yl, 6-methoxypyridin-2-yl, 2-ethoxypyridin-3-yl,6-ethoxypyridin-2-yl, 6-(propan-2-yloxy)pyridin-2-yl,6-(dimethylamino)pyridin-3-yl, 6-(methylsulfanyl)pyridin-2-yl,6-(cyclobutyloxy)pyridin-2-yl, 6-(pyrrolidin-1-yl)pyridin-2-yl,2-methylpyrimidin-4-yl, 2-(propan-2-yl)pyrimidin-4-yl,2-cyclopropylpyrimidin-4-yl, 1-methyl-1H-indol-3-yl,2-methyl-2H-indazol-5-yl, 2-methyl-1-benzofuran-5-yl,1-methyl-1H-benzimidazol-2-yl, 4-methyl-1H-benzimidazol-2-yl5-fluoro-1H-benzimidazol-2-yl, 4-fluoro-1,3-benzoxazol-2-yl,5-fluoro-1,3-benzoxazol-2-yl, 4-chloro-1,3-benzoxazol-2-yl,4-iodo-1,3-benzoxazol-2-yl, 2-methyl-1,3-benzoxazol-6-yl,4-methyl-1,3-benzoxazol-2-yl, 4-(trifluoromethyl)-1,3-benzoxazol-2-yl,7-(trifluoromethyl)-1,3-benzoxazol-2-yl, 2-methyl-1,3-benzothiazol-2-yl,2-methyl-1,3-benzothiazol-5-yl, 2-methyl-1,3-benzothiazol-6-yl,4-chloro-1,3-benzothiazol-2-yl, 7-chloro-1,3-benzothiazol-2-yl,4-(trifluoromethyl)-1,3-benzothiazol-2-yl,5-methylfuro[3,2-b]pyridin-2-yl, 4,6-dimethylfuro[3,2-c]pyridin-2-yl,5,7-dimethylfuro[2,3-c]pyridin-2-yl,4,6-dimethylthieno[3,2-c]pyridin-2-yl,2,4-dimethylthieno[2,3-d]pyrimidin-6-yl,1-methylpyrrolo[1,2-a]pyrazin-7-yl, 3-methylpyrrolo[1,2-a]pyrazin-7-yl,1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl,2-methylpyrrolo[1,2-b]pyridazin-2-yl,4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl,5-methylpyrazolo[1,5-a]pyridin-2-yl,4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl,2-chloroimidazo[2,1-b][1,3]thiazol-6-yl,2-methylimidazo[2,1-b][1,3]thiazol-6-yl,3-methylimidazo[2,1-b][1,3]thiazol-6-yl,2-ethylimidazo[2,1-b][1,3]thiazol-6-yl,2-methylimidazo[2,1-b][1,3,4]thiadiazol-6-yl,6-cyanoimidazo[1,2-a]pyridin-2-yl (also referred to as2-imidazo[1,2-a]pyridine-6-carbonitrile),6-fluoroimidazo[1,2-a]pyridin-2-yl, 8-fluoroimidazo[1,2-a]pyridin-2-yl,6,8-difluoroimidazo[1,2-a]pyridin-2-yl,7-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl,8-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl,6-chloroimidazo[1,2-a]pyridin-2-yl, 7-chloroimidazo[1,2-a]pyridin-2-yl,8-chloroimidazo[1,2-a]pyridin-2-yl, 8-bromoimidazo[1,2-a]pyridin-2-yl,2-methylimidazo[1,2-a]pyridin-2-yl, 5-methylimidazo[1,2-a]pyridin-2-yl,6-methylimidazo[1,2-a]pyridin-2-yl, 7-methylimidazo[1,2-a]pyridin-2-yl,8-methylimidazo[1,2-a]pyridin-2-yl, 7-ethylimidazo[1,2-a]pyridin-2-yl,8-ethylimidazo[1,2-a]pyridin-2-yl,6,8-dimethylimidazo[1,2-a]pyridin-2-yl,8-ethyl-6-methylimidazo[1,2-a]pyridin-2-yl,7-methoxyimidazo[1,2-a]pyridin-2-yl,8-methoxyimidazo[1,2-a]pyridin-2-yl,6-fluoro-8-methylimidazo[1,2-a]pyridin-2-yl,8-fluoro-6-methylimidazo[1,2-a]pyridin-2-yl,8-chloro-6-methylimidazo[1,2-a]pyridin-2-yl,6-methyl-8-nitroimidazo[1,2-a]pyridin-2-yl,8-cyclopropylimidazo[1,2-a]pyridin-2-yl,2-methylimidazo[1,2-a]pyridin-6-yl, 2-ethylimidazo[1,2-a]pyridin-6-yl,2,3-dimethylimidazo[1,2-a]pyridin-6-yl,2,8-dimethylimidazo[1,2-a]pyridin-6-yl,2-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl,8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl,8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl,6-fluoroimidazo[1,2-a]pyrimidin-2-yl,6-chloroimidazo[1,2-a]pyrimidin-2-yl,6-methylimidazo[1,2-a]pyrimidin-2-yl,7-methylimidazo[1,2-a]pyrimidin-2-yl,2-methylimidazo[1,2-a]pyrimidin-6-yl,6-methylimidazo[1,2-b]pyridazin-2-yl,2-methyl-3-(1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-b]pyridazin-6-yl,6-methylimidazo[1,2-a]pyrazin-2-yl, 8-methylimidazo[1,2-a]pyrazin-2-yl,6,8-dimethylimidazo[1,2-a]pyrazin-2-yl,6-chloro-8-methylimidazo[1,2-a]pyrazin-2-yl,6-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyrazin-2-yl,8-(methylsulfanyl)imidazo[1,2-a]pyrazin-2-yl,2-methylimidazo[2,1-b][1,3]thiazol-6-yl,3-methylimidazo[2,1-b][1,3]thiazol-6-yl or2-methylimidazo[2,1-b][1,3,4]thiadiazol-6-yl.

In another embodiment of the use of a compound of Formula (I),

R₂ is heteroaryl selected from thienyl, 1H-pyrazolyl, 1H-imidazolyl,1,3-thiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, pyridinyl,pyrimidinyl, 1H-indolyl, 2H-indolyl, 1H-indazolyl, 2H-indazolyl,indolizinyl, benzofuranyl, benzothienyl, 1H-benzimidazolyl,1,3-benzothiazolyl, 1,3-benzoxazolyl, 9H-purinyl; wherein, each instanceof heteroaryl is optionally substituted with R₆ and R₇ substituents.

In another embodiment of the use of a compound of Formula (I),

R₂ is heteroaryl selected from furo[3,2-b]pyridinyl,furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl, thieno[3,2-c]pyridinyl,thieno[2,3-d]pyrimidinyl, 1H-pyrrolo[2,3-b]pyridinyl,1H-pyrrolo[2,3-c]pyridinyl, pyrrolo[1,2-a]pyrimidinyl,pyrrolo[1,2-a]pyrazinyl, pyrrolo[1,2-b]pyridazinyl,pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrazinyl,imidazo[1,2-a]pyridinyl, imidazo[1,2-a]pyrimidinyl,imidazo[1,2-c]pyrimidinyl, imidazo[1,2-b]pyridazinyl,imidazo[1,2-a]pyrazinyl, imidazo[2,1-b][1,3]thiazolyl,imidazo[2,1-b][1,3,4]thiadiazolyl, [1,3]oxazolo[4,5-b]pyridinyl orquinoxalinyl; wherein, each instance of heteroaryl is optionallysubstituted with R₆ and R₇ substituents.

In one embodiment of the use of a compound of Formula (I), R₂ isheteroaryl-amino, wherein heteroaryl is selected from pyridinyl orpyrimidinyl; and, wherein, each instance of heteroaryl is optionallysubstituted with R₆ and R₇ substituents.

In another embodiment of the use of a compound of Formula (I), R₂ isheteroaryl-amino selected from pyridin-2-yl-amino, pyridin-3-yl-amino orpyrimidin-2-yl-amino; wherein, each instance of heteroaryl is optionallysubstituted with R₆ and R₇ substituents.

In one embodiment of the use of a compound of Formula (I), R₆ isselected from halogen, hydroxy, cyano, nitro, C₁₋₈alkyl, halo-C₁₋₈alkyl,hydroxy-C₁₋₈alkyl, C₁₋₈alkoxy, halo-C₁₋₈alkoxy, C₁₋₈alkoxy-C₁₋₈alkyl,(C₁₋₈alkyl)₂-amino or C₁₋₈alkyl-thio; wherein, halogen and halo isselected from fluoro, chloro, bromo or iodo.

In one embodiment of the use of a compound of Formula (I), R₆ isC₁₋₈alkyl selected from methyl, ethyl, propyl, isopropyl or tert-butyl.

In another embodiment of the use of a compound of Formula (I), R₆ isC₁₋₈alkyl selected from ethyl, propyl, isopropyl or tert-butyl.

In one embodiment of the use of a compound of Formula (I), R₆ isC₂₋₈alkenyl selected from ethenyl, allyl or buta-1,3-dienyl.

In another embodiment of the use of a compound of Formula (I), R₆ isC₂₋₈alkenyl selected from ethenyl or allyl.

In one embodiment of the use of a compound of Formula (I), R₆ ishalo-C₁₋₈alkyl selected from trihalo-methyl, dihalo-methyl, halo-methyl,trihalo-ethyl, dihalo-ethyl, halo-ethyl, trihalo-propyl, dihalo-propylor halo-propyl; wherein, halo is selected from fluoro, chloro, bromo oriodo.

In one embodiment of the use of a compound of Formula (I), R₆ ishydroxy-C₁₋₈alkyl selected from hydroxy-methyl, hydroxy-ethyl,hydroxy-propyl, dihydroxy-propyl, hydroxy-butyl or dihydroxy-butyl.

In another embodiment of the use of a compound of Formula (I), R₆ ishydroxy-C₁₋₈alkyl selected from hydroxy-methyl, dihydroxy-propyl,hydroxy-butyl or dihydroxy-butyl.

In one embodiment of the use of a compound of Formula (I), R₆ isC₁₋₈alkoxy selected from methoxy, ethoxy, propoxy or isopropoxy.

In one embodiment of the use of a compound of Formula (I), R₆ ishalo-C₁₋₈alkoxy selected from trihalo-methoxy, dihalo-methoxy,halo-methoxy, trihalo-ethoxy, dihalo-ethoxy, halo-ethoxy,trihalo-propoxy, dihalo-propoxy or halo-propoxy; wherein, halo isselected from fluoro, chloro, bromo or iodo.

In one embodiment of the use of a compound of Formula (I), R₇ isC₃₋₁₄cycloalkyl, C₃₋₁₄cycloalkyl-oxy, aryl, heterocyclyl or heteroaryl;wherein C₃₋₁₄cycloalkyl is selected from cyclopropyl or cyclobutoxy;wherein aryl is selected from phenyl; wherein heterocyclyl is selectedfrom oxetanyl, pyrrolidinyl or 1,2,3,6-tetrahydropyridinyl; and, whereinheteroaryl is selected from thienyl or pyridinyl.

In another embodiment of the use of a compound of Formula (I), R₇ isC₃₋₁₄cycloalkyl or C₃₋₁₄cycloalkyl-oxy, wherein each instance ofC₃₋₁₄cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl or cycloheptyl.

In another embodiment of the use of a compound of Formula (I), R₇ isC₃₋₈cycloalkyl or C₃₋₈cycloalkyl-oxy, wherein each instance ofC₃₋₈cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl or cycloheptyl.

In one embodiment of the use of a compound of Formula (I), R₇ is arylselected from phenyl.

In one embodiment of the use of a compound of Formula (I), R₇ isheterocyclyl selected from oxetanyl, pyrrolidinyl or1,2,3,6-tetrahydropyridinyl.

In another embodiment of the use of a compound of Formula (I), R₇ isheterocyclyl selected from oxetan-3-yl, pyrrolidin-1-yl or1,2,3,6-tetrahydropyridin-4-yl.

In one embodiment of the use of a compound of Formula (I), R₇ isheteroaryl selected from thienyl or pyridinyl.

In another embodiment of the use of a compound of Formula (I), R₇ isheteroaryl selected from pyridinyl.

In one embodiment of the use of a compound of Formula (I), R₇ isheteroaryl selected from thien-2-yl or pyridin-2-yl.

In another embodiment of the use of a compound of Formula (I), R₇ isheteroaryl selected from pyridin-2-yl.

In one embodiment of the use of a compound of Formula (I), R_(c) ishydrogen or C₁₋₈alkyl.

In another embodiment of the use of a compound of Formula (I),

R₁ is heterocyclyl, heterocyclyl-C₁₋₈alkyl, heterocyclyl-C₁₋₈alkoxy,heterocyclyl-amino, (heterocyclyl)(C₁₋₈alkyl)amino,heterocyclyl-amino-C₁₋₈alkyl, heterocyclyl-C₁₋₈alkyl-amino,(heterocyclyl-C₁₋₈alkyl)₂-amino,(heterocyclyl-C₁₋₈alkyl)(C₁₋₈alkyl)amino,heterocyclyl-C₁₋₈alkyl-amino-C₁₋₈alkyl,(heterocyclyl-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,(heterocyclyl-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl, heterocyclyl-oxy,heterocyclyl-carbonyl, heterocyclyl-carbonyl-oxy, C₃₋₁₄cycloalkyl,aryl-C₁₋₈alkyl-amino, (aryl-C₁₋₈alkyl)₂-amino,(aryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino, aryl-C₁₋₈alkyl-amino-C₁₋₈alkyl,(aryl-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,(aryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl, heteroaryl,heteroaryl-C₁₋₈alkyl, heteroaryl-C₁₋₈alkoxy, heteroaryl-amino,heteroaryl-C₁₋₈alkyl-amino, (heteroaryl-C₁₋₈alkyl)₂-amino,(heteroaryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino,heteroaryl-C₁₋₈alkyl-amino-C₁₋₈alkyl,(heteroaryl-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl or(heteroaryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl; wherein, each instanceof heterocyclyl, C₃₋₁₄cycloalkyl, aryl and heteroaryl is optionallysubstituted with R₃ and R₄ substituents; and,

wherein, heterocyclyl is selected from azetidinyl, tetrahydrofuranyl,pyrrolidinyl, piperidinyl, piperazinyl, 1,4-diazepanyl,1,2,5,6-tetrahydropyridinyl, 1,2,3,6-tetrahydropyridinyl,hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl,(3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl,(3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl,hexahydropyrrolo[3,4-b]pyrrol-(2H)-yl,(3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-(2H)-yl,hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl,(3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl,octahydro-5H-pyrrolo[3,2-c]pyridinyl,octahydro-6H-pyrrolo[3,4-b]pyridinyl,(4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridinyl,(4aS,7aS)-octahydro-6H-pyrrolo[3,4-b]pyridinyl,hexahydropyrrolo[1,2-a]pyrazin-(2H)-one,hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl,(7R,8aS)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl,(8aS)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl,(8aR)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl,(8aS)-octahydropyrrolo[1,2-a]pyrazin-(1H)-yl,(8aR)-octahydropyrrolo[1,2-a]pyrazin-(1H)-yl,octahydro-2H-pyrido[1,2-a]pyrazinyl, 3-azabicyclo[3.1.0]hexyl,(1R,5S)-3-azabicyclo[3.1.0]hexyl, 8-azabicyclo[3.2.1]octyl,(1R,5S)-8-azabicyclo[3.2.1]octyl, 8-azabicyclo[3.2.1]oct-2-enyl,(1R,5S)-8-azabicyclo[3.2.1]oct-2-enyl, 9-azabicyclo[3.3.1]nonyl,(1R,5S)-9-azabicyclo[3.3.1]nonyl, 2,5-diazabicyclo[2.2.1]heptyl,(1S,4S)-2,5-diazabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.2]octyl,3,8-diazabicyclo[3.2.1]octyl, (1R,5S)-3,8-diazabicyclo[3.2.1]octyl,1,4-diazabicyclo[3.2.2]nonyl, azaspiro[3.3]heptyl,2,6-diazaspiro[3.3]heptyl, 2,7-diazaspiro[3.5]nonyl,5,8-diazaspiro[3.5]nonyl, 2,7-diazaspiro[4.4]nonyl or6,9-diazaspiro[4.5]decyl.

In another embodiment of the use of a compound of Formula (I),

R₂ is aryl, aryl-amino, aryl-amino-carbonyl, heterocyclyl, heteroaryl orheteroaryl-amino;

wherein, aryl is phenyl;

wherein, heterocyclyl is selected from 1,2,3,6-tetrahydropyridinyl,1,3-benzodioxolyl or 2,3-dihydro-1,4-benzodioxinyl;

wherein, heteroaryl is selected from thienyl, 1H-pyrazolyl,1H-imidazolyl, 1,3-thiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl,pyridinyl, pyrimidinyl, 1H-indolyl, 2H-indolyl, 1H-indazolyl,2H-indazolyl, indolizinyl, benzofuranyl, benzothienyl,1H-benzimidazolyl, 1,3-benzothiazolyl, 1,3-benzoxazolyl, 9H-purinyl,furo[3,2-b]pyridinyl, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl,thieno[3,2-c]pyridinyl, thieno[2,3-d]pyrimidinyl,1H-pyrrolo[2,3-b]pyridinyl, 1H-pyrrolo[2,3-c]pyridinyl,pyrrolo[1,2-a]pyrimidinyl, pyrrolo[1,2-a]pyrazinyl,pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridinyl,pyrazolo[1,5-a]pyrazinyl, imidazo[1,2-a]pyridinyl,imidazo[1,2-a]pyrimidinyl, imidazo[1,2-c]pyrimidinyl,imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl,imidazo[2,1-b][1,3]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl,[1,3]oxazolo[4,5-b]pyridinyl or quinoxalinyl; and, wherein, eachinstance of aryl, heterocyclyl and heteroaryl is optionally substitutedwith R₆ and R₇ substituents.

In another embodiment of the use of a compound of Formula (I),

R₁ is heterocyclyl, heterocyclyl-C₁₋₈alkyl, heterocyclyl-C₁₋₈alkoxy,heterocyclyl-amino, (heterocyclyl)(C₁₋₈alkyl)amino,heterocyclyl-amino-C₁₋₈alkyl, heterocyclyl-C₁₋₈alkyl-amino,(heterocyclyl-C₁₋₈alkyl)₂-amino,(heterocyclyl-C₁₋₈alkyl)(C₁₋₈alkyl)amino,heterocyclyl-C₁₋₈alkyl-amino-C₁₋₈alkyl,(heterocyclyl-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,(heterocyclyl-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl, heterocyclyl-oxy,heterocyclyl-carbonyl, heterocyclyl-carbonyl-oxy, C₃₋₁₄cycloalkyl,aryl-C₁₋₈alkyl-amino, (aryl-C₁₋₈alkyl)₂-amino,(aryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino, aryl-C₁₋₈alkyl-amino-C₁₋₈alkyl,(aryl-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,(aryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl, heteroaryl,heteroaryl-C₁₋₈alkyl, heteroaryl-C₁₋₈alkoxy, heteroaryl-amino,heteroaryl-C₁₋₈alkyl-amino, (heteroaryl-C₁₋₈alkyl)₂-amino,(heteroaryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino,heteroaryl-C₁₋₈alkyl-amino-C₁₋₈alkyl,(heteroaryl-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl or(heteroaryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl;

wherein, heterocyclyl is selected from azetidinyl, tetrahydrofuranyl,pyrrolidinyl, piperidinyl, piperazinyl, 1,4-diazepanyl,1,2,5,6-tetrahydropyridinyl, 1,2,3,6-tetrahydropyridinyl,hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl,(3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl,(3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl,hexahydropyrrolo[3,4-b]pyrrol-(2H)-yl,(3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-(2H)-yl,hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl,(3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl,octahydro-5H-pyrrolo[3,2-c]pyridinyl,octahydro-6H-pyrrolo[3,4-b]pyridinyl,(4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridinyl,(4aS,7aS)-octahydro-6H-pyrrolo[3,4-b]pyridinyl,hexahydropyrrolo[1,2-a]pyrazin-(2H)-one,hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl,(7R,8aS)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl,(8aS)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl,(8aR)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl,(8aS)-octahydropyrrolo[1,2-a]pyrazin-(1H)-yl,(8aR)-octahydropyrrolo[1,2-a]pyrazin-(1H)-yl,octahydro-2H-pyrido[1,2-a]pyrazinyl, 3-azabicyclo[3.1.0]hexyl,(1R,5S)-3-azabicyclo[3.1.0]hexyl, 8-azabicyclo[3.2.1]octyl,(1R,5S)-8-azabicyclo[3.2.1]octyl, 8-azabicyclo[3.2.1]oct-2-enyl,(1R,5S)-8-azabicyclo[3.2.1]oct-2-enyl, 9-azabicyclo[3.3.1]nonyl,(1R,5S)-9-azabicyclo[3.3.1]nonyl, 2,5-diazabicyclo[2.2.1]heptyl,(1S,4S)-2,5-diazabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.2]octyl,3,8-diazabicyclo[3.2.1]octyl, (1R,5S)-3,8-diazabicyclo[3.2.1]octyl,1,4-diazabicyclo[3.2.2]nonyl, azaspiro[3.3]heptyl,2,6-diazaspiro[3.3]heptyl, 2,7-diazaspiro[3.5]nonyl,5,8-diazaspiro[3.5]nonyl, 2,7-diazaspiro[4.4]nonyl or6,9-diazaspiro[4.5]decyl; and, wherein, each instance of heterocyclyl,C₃₋₁₄cycloalkyl, aryl and heteroaryl is optionally substituted with R₃and R₄ substituents; and

R₂ is aryl, aryl-amino, aryl-amino-carbonyl, heterocyclyl, heteroaryl orheteroaryl-amino;

wherein, heterocyclyl is selected from 1,2,3,6-tetrahydropyridin-4-yl,1,3-benzodioxol-5-yl or 2,3-dihydro-1,4-benzodioxin-6-yl;

wherein, heteroaryl is selected from thienyl, 1H-pyrazolyl,1H-imidazolyl, 1,3-thiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl,pyridinyl, pyrimidinyl, 1H-indolyl, 2H-indolyl, 1H-indazolyl,2H-indazolyl, indolizinyl, benzofuranyl, benzothienyl,1H-benzimidazolyl, 1,3-benzothiazolyl, 1,3-benzoxazolyl, 9H-purinyl,furo[3,2-b]pyridinyl, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl,thieno[3,2-c]pyridinyl, thieno[2,3-d]pyrimidinyl,1H-pyrrolo[2,3-b]pyridinyl, 1H-pyrrolo[2,3-c]pyridinyl,pyrrolo[1,2-a]pyrimidinyl, pyrrolo[1,2-a]pyrazinyl,pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridinyl,pyrazolo[1,5-a]pyrazinyl, imidazo[1,2-a]pyridinyl,imidazo[1,2-a]pyrimidinyl, imidazo[1,2-c]pyrimidinyl,imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl,imidazo[2,1-b][1,3]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl,[1,3]oxazolo[4,5-b]pyridinyl or quinoxalinyl; and, wherein, eachinstance of heterocyclyl and heteroaryl is optionally substituted withR₆ and R₇ substituents.

In another embodiment of the use of a compound of Formula (I),

R₁ is C₁₋₈alkyl, amino, C₁₋₈alkyl-amino, (C₁₋₈alkyl)₂-amino,C₁₋₈alkoxy-C₁₋₈alkyl-amino, (C₁₋₈alkoxy-C₁₋₈alkyl)₂-amino,(C₁₋₈alkoxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino, amino-C₁₋₈alkyl,C₁₋₈alkyl-amino-C₁₋₈alkyl, (C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,C₁₋₈alkoxy-C₁₋₈alkyl-amino-C₁₋₈alkyl,(C₁₋₈alkoxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,(C₁₋₈alkoxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl, amino-C₁₋₈alkyl-amino,(amino-C₁₋₈alkyl)₂-amino, (amino-C₁₋₈alkyl)(C₁₋₈alkyl)amino,C₁₋₈alkyl-amino-C₁₋₈alkyl-amino, (C₁₋₈alkyl-amino-C₁₋₈alkyl)₂-amino,(C₁₋₈alkyl-amino-C₁₋₈alkyl)(C₁₋₈alkyl)amino,(C₁₋₈alkyl)₂-amino-C₁₋₈alkyl-amino,[(C₁₋₈alkyl)₂-amino-C₁₋₈alkyl](C₁₋₈alkyl)amino, amino-C₁₋₈alkoxy,C₁₋₈alkyl-amino-C₁₋₈alkoxy, (C₁₋₈alkyl)₂-amino-C₁₋₈alkoxy,C₁₋₈alkoxy-C₁₋₈alkyl-amino-C₁₋₈alkoxy,(C₁₋₈alkoxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkoxy,(C₁₋₈alkoxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkoxy, amino-C₂₋₈alkenyl,C₁₋₈alkyl-amino-C₂₋₈alkenyl, (C₁₋₈alkyl)₂-amino-C₂₋₈alkenyl,amino-C₂₋₈alkynyl, C₁₋₈alkyl-amino-C₂₋₈alkynyl,(C₁₋₈alkyl)₂-amino-C₂₋₈alkynyl, halo-C₁₋₈alkyl-amino,(halo-C₁₋₈alkyl)₂-amino, (halo-C₁₋₈alkyl)(C₁₋₈alkyl)amino,hydroxy-C₁₋₈alkyl, hydroxy-C₁₋₈alkoxy-C₁₋₈alkyl,hydroxy-C₁₋₈alkyl-amino, (hydroxy-C₁₋₈alkyl)₂-amino,(hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino, hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkyl,(hydroxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,(hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl,hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkoxy,(hydroxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkoxy,(hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkoxy,hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkyl-amino,(hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkyl)₂-amino,(hydroxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl-amino,(hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkyl)(C₁₋₈alkyl)amino,(hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl-amino,[(hydroxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl](C₁₋₈alkyl)amino or[(hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl](C₁₋₈alkyl)amino; and

R₂ is aryl, aryl-amino, aryl-amino-carbonyl, heterocyclyl, heteroaryl orheteroaryl-amino, wherein, each instance of aryl, heterocyclyl andheteroaryl is optionally substituted with R₆ and R₇ substituents.

In another embodiment of the use of a compound of Formula (I),

R₁ is heterocyclyl, heterocyclyl-C₁₋₈alkyl, heterocyclyl-C₁₋₈alkoxy,heterocyclyl-amino, (heterocyclyl)(C₁₋₈alkyl)amino,heterocyclyl-amino-C₁₋₈alkyl, heterocyclyl-C₁₋₈alkyl-amino,(heterocyclyl-C₁₋₈alkyl)₂-amino,(heterocyclyl-C₁₋₈alkyl)(C₁₋₈alkyl)amino,heterocyclyl-C₁₋₈alkyl-amino-C₁₋₈alkyl,(heterocyclyl-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,(heterocyclyl-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl, heterocyclyl-oxy,heterocyclyl-carbonyl, heterocyclyl-carbonyl-oxy, C₃₋₁₄cycloalkyl,aryl-C₁₋₈alkyl-amino, (aryl-C₁₋₈alkyl)₂-amino,(aryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino, aryl-C₁₋₈alkyl-amino-C₁₋₈alkyl,(aryl-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,(aryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl, heteroaryl,heteroaryl-C₁₋₈alkyl, heteroaryl-C₁₋₈alkoxy, heteroaryl-amino,heteroaryl-C₁₋₈alkyl-amino, (heteroaryl-C₁₋₈alkyl)₂-amino,(heteroaryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino,heteroaryl-C₁₋₈alkyl-amino-C₁₋₈alkyl,(heteroaryl-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl or(heteroaryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl; wherein, each instanceof heterocyclyl, C₃₋₁₄cycloalkyl, aryl and heteroaryl is optionallysubstituted with R₃ and R₄ substituents; and

R₂ is aryl, aryl-amino, aryl-amino-carbonyl, heterocyclyl, heteroaryl orheteroaryl-amino, wherein, each instance of aryl, heterocyclyl andheteroaryl is optionally substituted with R₆ and R₇ substituents.

In another embodiment of the use of a compound of Formula (I),

R₁ is heterocyclyl, heterocyclyl-C₁₋₈alkyl, heterocyclyl-C₁₋₈alkoxy,heterocyclyl-amino, (heterocyclyl)(C₁₋₈alkyl)amino,heterocyclyl-amino-C₁₋₈alkyl, heterocyclyl-C₁₋₈alkyl-amino,(heterocyclyl-C₁₋₈alkyl)₂-amino,(heterocyclyl-C₁₋₈alkyl)(C₁₋₈alkyl)amino,heterocyclyl-C₁₋₈alkyl-amino-C₁₋₈alkyl,(heterocyclyl-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,(heterocyclyl-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl, heterocyclyl-oxy,heterocyclyl-carbonyl or heterocyclyl-carbonyl-oxy; wherein, eachinstance of heterocyclyl is optionally substituted with R₃ and R₄substituents; and

R₂ is aryl, aryl-amino, aryl-amino-carbonyl, heterocyclyl, heteroaryl orheteroaryl-amino, wherein, each instance of aryl, heterocyclyl andheteroaryl is optionally substituted with R₆ and R₇ substituents.

In another embodiment of the use of a compound of Formula (I),

R₁ is heterocyclyl optionally substituted with R₃ and R₄ substituents;and

R₂ is aryl, aryl-amino, aryl-amino-carbonyl, heterocyclyl, heteroaryl orheteroaryl-amino, wherein, each instance of aryl, heterocyclyl andheteroaryl is optionally substituted with R₆ and R₇ substituents.

In another embodiment of the use of a compound of Formula (I),

R₁ is C₃₋₁₄cycloalkyl optionally substituted with R₃ and R₄substituents; and

R₂ is aryl, aryl-amino, aryl-amino-carbonyl, heterocyclyl, heteroaryl orheteroaryl-amino, wherein, each instance of aryl, heterocyclyl andheteroaryl is optionally substituted with R₆ and R₇ substituents.

In another embodiment of the use of a compound of Formula (I),

R₁ is aryl-C₁₋₈alkyl-amino, (aryl-C₁₋₈alkyl)₂-amino,(aryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino, aryl-C₁₋₈alkyl-amino-C₁₋₈alkyl,(aryl-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl or(aryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl; wherein, each instance ofaryl is optionally substituted with R₃ and R₄ substituents; and

R₂ is aryl, aryl-amino, aryl-amino-carbonyl, heterocyclyl, heteroaryl orheteroaryl-amino, wherein, each instance of aryl, heterocyclyl andheteroaryl is optionally substituted with R₆ and R₇ substituents.

In another embodiment of the use of a compound of Formula (I),

R₁ is aryl-C₁₋₈alkyl-amino optionally substituted with R₃ and R₄substituents; and

R₂ is aryl, aryl-amino, aryl-amino-carbonyl, heterocyclyl, heteroaryl orheteroaryl-amino, wherein, each instance of aryl, heterocyclyl andheteroaryl is optionally substituted with R₆ and R₇ substituents.

In another embodiment of the use of a compound of Formula (I),

R₁ is heteroaryl, heteroaryl-C₁₋₈alkyl, heteroaryl-C₁₋₈alkoxy,heteroaryl-amino, heteroaryl-C₁₋₈alkyl-amino,(heteroaryl-C₁₋₈alkyl)₂-amino, (heteroaryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino,heteroaryl-C₁₋₈alkyl-amino-C₁₋₈alkyl,(heteroaryl-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl or(heteroaryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl; wherein, each instanceof heterocyclyl, C₃₋₁₄cycloalkyl, aryl and heteroaryl is optionallysubstituted with R₃ and R₄ substituents; and

R₂ is aryl, aryl-amino, aryl-amino-carbonyl, heterocyclyl, heteroaryl orheteroaryl-amino, wherein, each instance of aryl, heterocyclyl andheteroaryl is optionally substituted with R₆ and R₇ substituents.

In another embodiment of the use of a compound of Formula (I),

R₁ is heteroaryl optionally substituted with R₃ and R₄ substituents; and

R₂ is aryl, aryl-amino, aryl-amino-carbonyl, heterocyclyl, heteroaryl orheteroaryl-amino, wherein, each instance of aryl, heterocyclyl andheteroaryl is optionally substituted with R₆ and R₇ substituents.

In one embodiment, the compound of Formula (I), used in a methoddisclosed herein, is a compound selected from Formula (II), Formula(III), Formula (IV), Formula (V), Formula (VI), Formula (VII), Formula(VIII), Formula (IX), Formula (X), Formula (XI), Formula (XII), Formula(XIII) or Formula (XIV):

or a form thereof.

In an embodiment of the use of the compound of Formula (I), w₃ is C—R₁,w₆ is C—R₂, w₁, w₄, w₅ and w₇ are independently C—R_(a), or N and w₂ isC—R_(b) or N.

In another embodiment of the use of the compound of Formula (I), w₃ isC—R₂, w₆ is C—R₁, w₁, w₄, w₅ and w₇ are independently C—R_(a), or N andw₂ is C—R_(b) or N.

In another embodiment of the use of the compound of Formula (I), w₄ isC—R₁, w₇ is C—R₂, w₁, w₃ and w₅ are independently C—R_(a) or N, w₂ isC—R_(b) or N and w₆ is C—R_(c) or N.

In another embodiment of the use of the compound of Formula (I), w₄ isC—R₂, w₇ is C—R₁, w₁, w₃ and w₅ are independently C—R_(a) or N, w₂ isC—R_(b) or N and w₆ is C—R_(c) or N.

In an embodiment of the use of the compound of Formula (II), w₃ is C—R₁,w₆ is C—R₂, w₄, w₅ and w₇ are independently C—R_(a) or N and w₂ isC—R_(b) or N.

In another embodiment of the use of the compound of Formula (II), w₃ isC—R₂, w₆ is C—R₁, w₄, w₅ and w₇ are independently C—R_(a) or N and w₂ isC—R_(b) or N.

In another embodiment of the use of the compound of Formula (II), w₄ isC—R₁, w₇ is C—R₂, w₃ and w₅ are independently C—R_(a) or N, w₂ isC—R_(b) or N and w₆ is C—R_(c) or N.

In another embodiment of the use of the compound of Formula (II), w₄ isC—R₂, w₇ is C—R₁, w₃ and w₅ are independently C—R_(a) or N, w₂ isC—R_(b) or N and w₆ is C—R_(c) or N.

In an embodiment of the use of the compound of Formula (III), w₃ isC—R₁, w₆ is C—R₂ and w₁, w₄, w₅ and w₇ are independently C—R_(a) or N.

In another embodiment of the use of the compound of Formula (III), w₃ isC—R₂, w₆ is C—R₁ and w₁, w₄, w₅ and w₇ are independently C—R_(a) or N.

In another embodiment of the use of the compound of Formula (III), w₄ isC—R₁, w₇ is C—R₂, w₁, w₃ and w₅ are independently C—R_(a) or N and w₆ isC—R_(c) or N.

In another embodiment of the use of the compound of Formula (III), w₄ isC—R₂, w₇ is C—R₁, w₁, w₃ and w₅ are independently C—R_(a) or N and w₆ isC—R_(c) or N.

In an embodiment of the use of the compound of Formula (IV), w₄ is C—R₁,w₇ is C—R₂, w₁ and w₅ are independently C—R_(a) or N, w₂ is C—R_(b) or Nand w₆ is C—R_(c) or N.

In another embodiment of the use of the compound of Formula (IV), w₄ isC—R₂, w₇ is C—R₁, w₁ and w₅ are independently C—R_(a) or N, w₂ isC—R_(b) or N and w₆ is C—R_(c) or N.

In an embodiment of the use of the compound of Formula (V), w₃ is C—R₁,w₆ is C—R₂, w₁, w₅ and w₇ are independently C—R_(a) or N and w₂ isC—R_(b) or N.

In another embodiment of the use of the compound of Formula (V), w₃ isC—R₂, w₆ is C—R₁, w₁, w₅ and w₇ are independently C—R_(a) or N and w₂ isC—R_(b) or N.

In an embodiment of the use of the compound of Formula (VI), w₃ is C—R₁,w₆ is C—R₂, w₁, w₄ and w₇ are independently C—R_(a) or N and w₂ isC—R_(b) or N.

In another embodiment of the use of the compound of Formula (VI), w₃ isC—R₂, w₆ is C—R₁, w₁, w₄ and w₇ are independently C—R_(a) or N and w₂ isC—R_(b) or N.

In another embodiment of the use of the compound of Formula (VI), w₄ isC—R₁, w₇ is C—R₂, w₁ and w₃ are independently C—R_(a) or N, w₂ isC—R_(b) or N and w₆ is C—R or N.

In another embodiment of the use of the compound of Formula (VI), w₄ isC—R₂, w₇ is C—R₁, w₁ and w₃ are independently C—R_(a) or N, w₂ isC—R_(b) or N and w₆ is C—R_(c) or N.

In another embodiment of the use of the compound of Formula (VII), w₄ isC—R₁, w₇ is C—R₂, w₁, w₃ and w₅ are C—R_(a) or N and w₂ is C—R_(b) or N.

In another embodiment of the use of the compound of Formula (VII), w₄ isC—R₂, w₇ is C—R₁, w₁, w₃ and w₅ are C—R_(a) or N and w₂ is C—R_(b) or N.

In another embodiment of the use of the compound of Formula (VIII), w₃is C—R₁, w₆ is C—R₂, w₁, w₄ and w₅ are C—R_(a) or N and w₂ is C—R_(b) orN.

In another embodiment of the use of the compound of Formula (VIII), w₃is C—R₂, w₆ is C—R₁, w₁, w₄ and w₅ are C—R_(a) or N and w₂ is C—R_(b) orN.

In an embodiment of the use of the compound of Formula (IX), w₃ is C—R₁,w₆ is C—R₂, w₄ and w₇ are independently C—R_(a) or N and w₂ is C—R_(b)or N.

In another embodiment of the use of the compound of Formula (IX), w₃ isC—R₂, w₆ is C—R₁, w₄ and w₇ are independently C—R_(a) or N and w₂ isC—R_(b) or N.

In another embodiment of the use of the compound of Formula (IX), w₄ isC—R₁, w₇ is C—R₂, w₂ is C—R_(b) or N, w₃ is C—R_(a) or N and w₆ isC—R_(c) or N.

In another embodiment of the use of the compound of Formula (IX), w₄ isC—R₂, w₇ is C—R₁, w₂ is C—R_(b) or N, w₃ is C—R_(a) or N and w₆ isC—R_(c) or N.

In an embodiment of the use of the compound of Formula (X), w₃ is C—R₁,w₆ is C—R₂, w₂ is C—R_(b) or N and w₅ and w₇ are independently C—R_(a)or N.

In another embodiment of the use of the compound of Formula (X), w₃ isC—R₂, w₆ is C—R₁, w₂ is C—R_(b) or N and w₅ and w₇ are independentlyC—R_(a) or N.

In an embodiment of the use of the compound of Formula (XI), w₄ is C—R₁,w₇ is C—R₂, w₂ is C—R_(b) or N, w₅ is C—R_(a) or N and w₆ is C—R_(c) orN.

In another embodiment of the use of the compound of Formula (XI), w₄ isC—R₂, w₇ is C—R₁, w₂ is C—R_(b) or N, w₅ is C—R_(a) or N and w₆ isC—R_(c) or N.

In an embodiment of the use of the compound of Formula (XII), w₃ isC—R₁, w₆ is C—R₂ and w₄, w₅ and w₇ are independently C—R_(a) or N.

In another embodiment of the use of the compound of Formula (XII), w₃ isC—R₂, w₆ is C—R₁ and w₄, w₅ and w₇ are independently C—R_(a) or N.

In another embodiment of the use of the compound of Formula (XII), w₄ isC—R₁, w₇ is C—R₂, w₃ and w₅ are independently C—R_(a) or N and w₆ isC—R_(c) or N.

In another embodiment of the use of the compound of Formula (XII), w₄ isC—R₂, w₇ is C—R₁, w₃ and w₅ are independently C—R_(a) or N and w₆ isC—R_(c) or N.

In an embodiment of the use of the compound of Formula (XIII), w₃ isC—R₁, w₆ is C—R₂, w₂ is C—R_(b) or N and w₄ and w₅ are independentlyC—R_(a) or N.

In another embodiment of the use of the compound of Formula (XIII), w₃is C—R₂, w₆ is C—R₁, w₂ is C—R_(b) or N and w₄ and w₅ are independentlyC—R_(a) or N.

In an embodiment of the use of the compound of Formula (XIV), w₄ isC—R₁, w₇ is C—R₂, w₂ is C—R_(b) or N and w₃ and w₅ are independentlyC—R_(a) or N.

In another embodiment of the use of the compound of Formula (XIV), w₄ isC—R₂, w₇ is C—R₁, w₂ is C—R_(b) or N and w₃ and w₅ are independentlyC—R_(a) or N.

In another embodiment, the compound of Formula (I) used in a methoddisclosed herein is a compound selected from Formula (II), Formula(III), Formula (IX), Formula (XI) or Formula (XII):

or a form thereof.

In another embodiment, the compound of Formula (I) used in a methoddisclosed herein is a compound of Formula (II):

or a form thereof.

In another embodiment, the compound of Formula (I) used in a methoddisclosed herein is a compound of Formula (III):

or a form thereof.

In another embodiment, the compound of Formula (I) used in a methoddisclosed herein is a compound of Formula (IV):

or a form thereof.

In another embodiment, the compound of Formula (I) used in a methoddisclosed herein is a compound of Formula (V):

or a form thereof.

In another embodiment, the compound of Formula (I) used in a methoddisclosed herein is a compound of Formula (VI):

or a form thereof.

In another embodiment, the compound of Formula (I) used in a methoddisclosed herein is a compound of Formula (VII):

or a form thereof.

In another embodiment, the compound of Formula (I) used in a methoddisclosed herein is a compound of Formula (VIII):

or a form thereof.

In another embodiment, the compound of Formula (I) used in a methoddisclosed herein is a compound of Formula (IX):

or a form thereof.

In another embodiment, the compound of Formula (I) used in a methoddisclosed herein is a compound of Formula (X):

or a form thereof.

In another embodiment, the compound of Formula (I) used in a methoddisclosed herein is a compound of Formula (XI):

or a form thereof.

In another embodiment, the compound of Formula (I) used in a methoddisclosed herein is a compound of Formula (XII):

or a form thereof.

In another embodiment, the compound of Formula (I) used in a methoddisclosed herein is a compound of Formula (XIII):

or a form thereof.

In another embodiment, the compound of Formula (I) used in a methoddisclosed herein is a compound of Formula (XIV):

or a form thereof.

In one embodiment, the compound of Formula (I), Formula (II), Formula(III), Formula (IV), Formula (V), Formula (VI), Formula (VII), Formula(VIII), Formula (IX), Formula (X), Formula (XI), Formula (XII), Formula(XIII) or Formula (XIV) used in a method disclosed herein is a compoundselected from Formula (Ia), Formula (IIa), Formula (IIIa), Formula(IVa), Formula (Va), Formula (VIa), Formula (VIIa), Formula (VIIIa),Formula (IXa), Formula (Xa), Formula (XIa), Formula (XIIa), Formula(XIIIa) or Formula (XIVa), respectively:

or a form thereof.

In an embodiment of the use of the compound of Formula (Ia), one of w₃,w₄, w₆ and w₇ is C—R₁ and one other of w₃, w₄, w₆ and w₇ is C—R₂,provided that,

when w₃ is C—R₁, then w₆ is C—R₂ and w₄ and w₇ are independently C—R_(a)or N; or,

when w₃ is C—R₂, then w₆ is C—R₁ and w₄ and w₇ are independently C—R_(a)or N; or,

when w₄ is C—R₁, then w₇ is C—R₂ and w₃ is C—R_(a) or N and w₆ isC—R_(c) or N; or,

when w₄ is C—R₂, then w₇ is C—R₁ and w₃ is C—R_(a) or N and w₆ isC—R_(c) or N.

In an embodiment of the use of the compound of Formula (IIa), one of w₃,w₄, w₆ and w₇ is C—R₁ and one other of w₃, w₄, w₆ and w₇ is C—R₂,provided that,

when w₃ is C—R₁, then w₆ is C—R₂ and w₄ and w₇ are independently C—R_(a)or N; or,

when w₃ is C—R₂, then w₆ is C—R₁ and w₄ and w₇ are independently C—R_(a)or N; or,

when w₄ is C—R₁, then w₇ is C—R₂ and w₃ is C—R_(a) or N and w₆ isC—R_(c) or N; or,

when w₄ is C—R₂, then w₇ is C—R₁ and w₃ is C—R_(a) or N and w₆ isC—R_(c) or N.

In an embodiment of the use of the compound of Formula (IIIa), one ofw₃, w₄, w₆ and w₇ is C—R₁ and one other of w₃, w₄, w₆ and w₇ is C—R₂,provided that,

when w₃ is C—R₁, then w₆ is C—R₂ and w₄ and w₇ are independently C—R_(a)or N; or,

when w₃ is C—R₂, then w₆ is C—R₁ and w₄ and w₇ are independently C—R_(a)or N; or,

when w₄ is C—R₁, then w₇ is C—R₂ and w₃ is C—R_(a) or N and w₆ isC—R_(c) or N; or,

when w₄ is C—R₂, then w₇ is C—R₁ and w₃ is C—R_(a) or N and w₆ isC—R_(c) or N.

In an embodiment of the use of the compound of Formula (IVa), one of w₄and w₇ is C—R₁ and the other is C—R₂, provided that, when w₄ is C—R₁,then w₇ is C—R₂; or, when w₄ is C—R₂, then w₇ is C—R₁.

In an embodiment of the use of the compound of Formula (Va), one of w₃and w₆ is C—R₁ and the other is C—R₂, provided that, when w₃ is C—R₁,then w₆ is C—R₂; or, when w₃ is C—R₂, then w₆ is C—R₁.

In an embodiment of the use of the compound of Formula (VIa), one of w₃,w₄, w₆ and w₇ is C—R₁ and one other of w₃, w₄, w₆ and w₇ is C—R₂,provided that,

when w₃ is C—R₁, then w₆ is C—R₂ and w₄ and w₇ are independently C—R_(a)or N; or,

when w₃ is C—R₂, then w₆ is C—R₁ and w₄ and w₇ are independently C—R_(a)or N; or,

when w₄ is C—R₁, then w₇ is C—R₂ and w₃ is C—R_(a) or N and w₆ isC—R_(c) or N; or,

when w₄ is C—R₂, then w₇ is C—R₁ and w₃ is C—R_(a) or N and w₆ isC—R_(c) or N.

In an embodiment of the use of the compound of Formula (VIIa), one of w₄and w₇ is C—R₁ and the other is C—R₂, provided that, when w₄ is C—R₁,then w₇ is C—R₂; or, when w₄ is C—R₂, then w₇ is C—R₁.

In an embodiment of the use of the compound of Formula (VIIIa), one ofw₃ and w₆ is C—R₁ and the other is C—R₂, provided that, when w₃ is C—R₁,then w₆ is C—R₂; or, when w₃ is C—R₂, then w₆ is C—R₁.

In an embodiment of the use of the compound of Formula (IXa), one of w₃,w₄, w₆ and w₇ is C—R₁ and one other of w₃, w₄, w₆ and w₇ is C—R₂,provided that,

when w₃ is C—R₁, then w₆ is C—R₂ and w₄ and w₇ are independently C—R_(a)or N; or,

when w₃ is C—R₂, then w₆ is C—R₁ and w₄ and w₇ are independently C—R_(a)or N; or,

when w₄ is C—R₁, then w₇ is C—R₂ and w₃ is C—R_(a) or N and w₆ isC—R_(c) or N; or,

when w₄ is C—R₂, then w₇ is C—R₁ and w₃ is C—R_(a) or N and w₆ isC—R_(c) or N.

In an embodiment of the use of the compound of Formula (Xa), one of w₃and w₆ is C—R₁ and the other is C—R₂, provided that, when w₃ is C—R₁,then w₆ is C—R₂; or, when w₃ is C—R₂, then w₆ is C—R₁.

In an embodiment of the use of the compound of Formula (XIa), one of w₄and w₇ is C—R₁ and the other is C—R₂, provided that, when w₄ is C—R₁,then w₇ is C—R₂; or, when w₄ is C—R₂, then w₇ is C—R₁.

In an embodiment of the use of the compound of Formula (XIIa), one ofw₃, w₄, w₆ and w₇ is C—R₁ and one other of w₃, w₄, w₆ and w₇ is C—R₂,provided that,

when w₃ is C—R₁, then w₆ is C—R₂ and w₄ and w₇ are independently C—R_(a)or N; or,

when w₃ is C—R₂, then w₆ is C—R₁ and w₄ and w₇ are independently C—R_(a)or N; or,

when w₄ is C—R₁, then w₇ is C—R₂ and w₃ is C—R_(a) or N and w₆ isC—R_(c) or N; or,

when w₄ is C—R₂, then w₇ is C—R₁ and w₃ is C—R_(a) or N and w₆ isC—R_(c) or N.

In an embodiment of the use of the compound of Formula (XIIIa), one ofw₃ and w₆ is C—R₁ and the other is C—R₂, provided that, when w₃ is C—R₁,then w₆ is C—R₂; or, when w₃ is C—R₂, then w₆ is C—R₁.

In an embodiment of the use of the compound of Formula (XIVa), one of w₄and w₇ is C—R₁ and the other is C—R₂, provided that, when w₄ is C—R₁,then w₇ is C—R₂; or, when w₄ is C—R₂, then w₇ is C—R₁.

In another embodiment, the compound of Formula (I), Formula (II),Formula (III), Formula (IX), Formula (XI) or Formula (XII), used in amethod disclosed herein, is a compound selected from Formula (Ia),Formula (IIa), Formula (IIIa), Formula (IXa), Formula (XIa) or Formula(XIIa), respectively:

or a form thereof.

In another embodiment, the compound of Formula (I) used in a methoddisclosed herein is a compound of Formula (Ia):

or a form thereof.

In another embodiment, the compound of Formula (II) used in a methoddisclosed herein is a compound of Formula (IIa):

or a form thereof.

In another embodiment, the compound of Formula (III) used in a methoddisclosed herein is a compound of Formula (IIIa):

or a form thereof.

In another embodiment, the compound of Formula (IV) used in a methoddisclosed herein is a compound of Formula (IVa):

or a form thereof.

In another embodiment, the compound of Formula (V) used in a methoddisclosed herein is a compound of Formula (Va):

or a form thereof.

In another embodiment, the compound of Formula (VI) used in a methoddisclosed herein is a compound of Formula (VIa):

or a form thereof.

In another embodiment, the compound of Formula (VII) used in a methoddisclosed herein is a compound of Formula (VIIa):

or a form thereof.

In another embodiment, the compound of Formula (VIII) used in a methoddisclosed herein is a compound of Formula (VIIIa):

or a form thereof.

In another embodiment, the compound of Formula (IX) used in a methoddisclosed herein is a compound of Formula (IXa):

or a form thereof.

In another embodiment, the compound of Formula (X) used in a methoddisclosed herein is a compound of Formula (Xa):

or a form thereof.

In another embodiment, the compound of Formula (XI) used in a methoddisclosed herein is a compound of Formula (XIa):

or a form thereof.

In another embodiment, the compound of Formula (XII) used in a methoddisclosed herein is a compound of Formula (XIIa):

or a form thereof.

In another embodiment, the compound of Formula (XIII) used in a methoddisclosed herein is a compound of Formula (XIIIa):

or a form thereof.

In another embodiment, the compound of Formula (XIV) used in a methoddisclosed herein is a compound of Formula (XIVa):

or a form thereof.

In one embodiment, the compound of Formula (Ia) used in a methoddisclosed herein is a compound of Formula (Ia1), Formula (Ia2), Formula(Ia3) or Formula (Ia4):

or a form thereof.

In one embodiment, the compound of Formula (IIa) used in a methoddisclosed herein is a compound of Formula (IIa1), Formula (IIa2),Formula (IIa3) or Formula (IIa4):

or a form thereof.

In one embodiment, the compound of Formula (IIIa) used in a methoddisclosed herein is a compound of Formula (IIIa1), Formula (IIIa2),Formula (IIIa3) or Formula (IIIa4):

or a form thereof.

In one embodiment, the compound of Formula (IVa) used in a methoddisclosed herein is a compound of Formula (IVa1) or Formula (IVa2):

or a form thereof.

In one embodiment, the compound of Formula (Va) used in a methoddisclosed herein is a compound of Formula (Va1) or Formula (Va2):

or a form thereof.

In one embodiment, the compound of Formula (VIa) used in a methoddisclosed herein is a compound of Formula (VIa1), Formula (VIa2),Formula (VIa3) or Formula (VIa4):

or a form thereof.

In one embodiment, the compound of Formula (VIIa) used in a methoddisclosed herein is a compound of Formula (VIIa1) or Formula (VIIa2):

or a form thereof.

In one embodiment, the compound of Formula (VIIIa) used in a methoddisclosed herein is a compound of Formula (VIIIa1) or Formula (VIIIa2):

or a form thereof.

In one embodiment, the compound of Formula (IXa) used in a methoddisclosed herein is a compound of Formula (IXa1), Formula (IXa2),Formula (IXa3) or Formula (IXa4):

or a form thereof.

In one embodiment, the compound of Formula (Xa) used in a methoddisclosed herein is a compound of Formula (Xa1) or Formula (Xa2):

or a form thereof.

In one embodiment, the compound of Formula (XIa) used in a methoddisclosed herein is a compound of Formula (XIa1) or Formula (XIa2):

or a form thereof.

In one embodiment, the compound of Formula (XIIa) used in a methoddisclosed herein is a compound of Formula (XIIa1), Formula (XIIa2),Formula (XIIa3) or Formula (XIIa4):

or a form thereof.

In one embodiment, the compound of Formula (XIIIa) used in a methoddisclosed herein is a compound of Formula (XIIIa1) or Formula (XIIIa2):

or a form thereof.

In one embodiment, the compound of Formula (XIVa) used in a methoddisclosed herein is a compound of Formula (XIVa1) or Formula (XIVa2):

or a form thereof.

In one embodiment, the compound of Formula (Ia) used in a methoddisclosed herein is a compound of Formula (Ia1):

or a form thereof.

In one embodiment, the compound of Formula (Ia) used in a methoddisclosed herein is a compound of Formula (Ia2):

or a form thereof.

In one embodiment, the compound of Formula (Ia) used in a methoddisclosed herein is a compound of Formula (Ia3):

or a form thereof.

In one embodiment, the compound of Formula (Ia) used in a methoddisclosed herein is a compound of Formula (Ia4):

or a form thereof.

In one embodiment, the compound of Formula (IIa) used in a methoddisclosed herein is a compound of Formula (IIa1):

or a form thereof.

In one embodiment, the compound of Formula (IIa) used in a methoddisclosed herein is a compound of Formula (IIa2):

or a form thereof.

In one embodiment, the compound of Formula (IIa) used in a methoddisclosed herein is a compound of Formula (IIa3):

or a form thereof.

In one embodiment, the compound of Formula (IIa) used in a methoddisclosed herein is a compound of Formula (IIa4):

or a form thereof.

In one embodiment, the compound of Formula (IIIa) used in a methoddisclosed herein is a compound of Formula (IIIa1):

or a form thereof.

In one embodiment, the compound of Formula (IIIa) used in a methoddisclosed herein is a compound of Formula (IIIa2):

or a form thereof.

In one embodiment, the compound of Formula (IIIa) used in a methoddisclosed herein is a compound of Formula (IIIa3):

or a form thereof.

In one embodiment, the compound of Formula (IIIa) used in a methoddisclosed herein is a compound of Formula (IIIa4):

or a form thereof.

In one embodiment, the compound of Formula (IVa) used in a methoddisclosed herein is a compound of Formula (IVa1):

or a form thereof.

In one embodiment, the compound of Formula (IVa) used in a methoddisclosed herein is a compound of Formula (IVa2):

or a form thereof.

In one embodiment, the compound of Formula (Va) used in a methoddisclosed herein is a compound of Formula (Va1):

or a form thereof.

In one embodiment, the compound of Formula (Va) used in a methoddisclosed herein is a compound of Formula (Va2):

or a form thereof.

In one embodiment, the compound of Formula (VIa) used in a methoddisclosed herein is a compound of Formula (VIa1):

or a form thereof.

In one embodiment, the compound of Formula (VIa) used in a methoddisclosed herein is a compound of Formula (VIa2):

or a form thereof.

In one embodiment, the compound of Formula (VIa) used in a methoddisclosed herein is a compound of Formula Formula (VIa3):

or a form thereof.

In one embodiment, the compound of Formula (VIa) used in a methoddisclosed herein is a compound of Formula (VIa4):

or a form thereof.

In one embodiment, the compound of Formula (VIIa) used in a methoddisclosed herein is a compound of Formula (VIIa1):

or a form thereof.

In one embodiment, the compound of Formula (VIIa) used in a methoddisclosed herein is a compound of Formula (VIIa2):

or a form thereof.

In one embodiment, the compound of Formula (VIIIa) used in a methoddisclosed herein is a compound of Formula (VIIIa1):

or a form thereof.

In one embodiment, the compound of Formula (VIIIa) used in a methoddisclosed herein is a compound of Formula (VIIIa2):

or a form thereof.

In one embodiment, the compound of Formula (IXa) used in a methoddisclosed herein is a compound of Formula (IXa1):

or a form thereof.

In one embodiment, the compound of Formula (IXa) used in a methoddisclosed herein is a compound of Formula (IXa2):

or a form thereof.

In one embodiment, the compound of Formula (IXa) used in a methoddisclosed herein is a compound of Formula (IXa3):

or a form thereof.

In one embodiment, the compound of Formula (IXa) used in a methoddisclosed herein is a compound of Formula (IXa4):

or a form thereof.

In one embodiment, the compound of Formula (Xa) used in a methoddisclosed herein is a compound of Formula (Xa1):

or a form thereof.

In one embodiment, the compound of Formula (Xa) used in a methoddisclosed herein is a compound of Formula (Xa2):

or a form thereof.

In one embodiment, the compound of Formula (XIa) used in a methoddisclosed herein is a compound of Formula (XIa1):

or a form thereof.

In one embodiment, the compound of Formula (XIa) used in a methoddisclosed herein is a compound of Formula (XIa2):

or a form thereof.

In one embodiment, the compound of Formula (XIIa) used in a methoddisclosed herein is a compound of Formula (XIIa1):

or a form thereof.

In one embodiment, the compound of Formula (XIIa) used in a methoddisclosed herein is a compound of Formula (XIIa2):

or a form thereof.

In one embodiment, the compound of Formula (XIIa) used in a methoddisclosed herein is a compound of Formula (XIIa3):

or a form thereof.

In one embodiment, the compound of Formula (XIIa) used in a methoddisclosed herein is a compound of Formula (XIIa4):

or a form thereof.

In one embodiment, the compound of Formula (XIIIa) used in a methoddisclosed herein is a compound of Formula (XIIIa1):

or a form thereof.

In one embodiment, the compound of Formula (XIIIa) used in a methoddisclosed herein is a compound of Formula (XIIIa2):

or a form thereof.

In one embodiment, the compound of Formula (XIVa) used in a methoddisclosed herein is a compound of Formula (XIVa1):

or a form thereof.

In one embodiment, the compound of Formula (XIVa) used in a methoddisclosed herein is a compound of Formula (XIVa2):

or a form thereof.

In another embodiment, the compound of Formula (I) used in a methoddisclosed herein is a compound selected from the group consisting of:

or a form thereof.

In another embodiment, the compound of Formula (I) used in a methoddisclosed herein is a compound selected from the group consisting of:

-   2-(4-methoxyphenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4-methoxyphenyl)-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4-methoxyphenyl)-7-[(3R)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-(4-methoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(1,4-diazepan-1-yl)-2-(4-methoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethoxyphenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethoxyphenyl)-7-(3,3-dimethylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethoxyphenyl)-7-[(3R)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethoxyphenyl)-7-(4-ethylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(1,4-diazepan-1-yl)-2-(3,4-dimethoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethoxyphenyl)-7-(4-methyl-1,4-diazepan-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4-methoxyphenyl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethoxyphenyl)-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethoxyphenyl)-7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethoxyphenyl)-7-(4-propylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4-methoxyphenyl)-7-(4-methyl-1,4-diazepan-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(3,3-dimethylpiperazin-1-yl)-2-(4-methoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(1,3-benzodioxol-5-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(1,3-benzodioxol-5-yl)-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(1,3-benzodioxol-5-yl)-7-[(3R)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(1,3-benzodioxol-5-yl)-7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3-methoxyphenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3-methoxyphenyl)-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3-methoxyphenyl)-7-[(3R)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-(3-methoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(4-ethylpiperazin-1-yl)-2-(3-methoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(1,4-diazepan-1-yl)-2-(3-methoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3-methoxyphenyl)-7-(4-methyl-1,4-diazepan-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(6-methylimidazo[1,2-a]pyridin-2-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethoxyphenyl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(2,3-dihydro-1,4-benzodioxin-6-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(2,3-dihydro-1,4-benzodioxin-6-yl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-phenyl-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[(3S)-3-methylpiperazin-1-yl]-2-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(2,3-dihydro-1,4-benzodioxin-6-yl)-7-[(3R)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(2,3-dihydro-1,4-benzodioxin-6-yl)-7-(3,3-dimethylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(2,3-dihydro-1,4-benzodioxin-6-yl)-7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(1,4-diazepan-1-yl)-2-(2,3-dihydro-1,4-benzodioxin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(2,3-dihydro-1,4-benzodioxin-6-yl)-7-(4-methyl-1,4-diazepan-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethoxyphenyl)-9-fluoro-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3-chlorophenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4-chlorophenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(piperazin-1-yl)-2-[3-(trifluoromethyl)phenyl]-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(piperazin-1-yl)-2-[4-(trifluoromethyl)phenyl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3-methylphenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4-fluorophenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4-nitrophenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethoxyphenyl)-9-fluoro-7-(piperidin-4-ylamino)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-[4-(dimethylamino)phenyl]-9-fluoro-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-[4-(dimethylamino)phenyl]-9-fluoro-7-[(3R)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(2-fluorophenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   3-(3,4-dimethoxyphenyl)-8-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-[4-(dimethylamino)phenyl]-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-[4-(dimethylamino)phenyl]-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethylphenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethylphenyl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-[3-(dimethylamino)phenyl]-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-[3-(dimethylamino)phenyl]-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-[4-(difluoromethoxy)phenyl]-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-[4-(difluoromethoxy)phenyl]-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3-fluorophenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3-nitrophenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4-methylphenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(2-fluoro-4,5-dimethoxyphenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(2-fluoro-4,5-dimethoxyphenyl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(3,4-dimethoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-[4-methoxy-3-(trifluoromethyl)phenyl]-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-[4-methoxy-3-(trifluoromethyl)phenyl]-7-[(3R)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-[4-methoxy-3-(trifluoromethyl)phenyl]-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethoxyphenyl)-9-methoxy-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,5-difluoro-4-hydroxyphenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3-fluoro-4-methoxyphenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   4-[4-oxo-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-2-yl]benzonitrile-   2-(6-methylimidazo[1,2-a]pyrazin-2-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(6-methylimidazo[1,2-a]pyrazin-2-yl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-[3-fluoro-5-(trifluoromethyl)phenyl]-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-[4-fluoro-3-(trifluoromethyl)phenyl]-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-[2-methoxy-3-(trifluoromethyl)phenyl]-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,5-difluorophenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(piperazin-1-yl)-2-[3-(trifluoromethoxy)phenyl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-[4-methoxy-3-(trifluoromethoxy)phenyl]-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-[4-hydroxy-3-(trifluoromethoxy)phenyl]-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-[4-methoxy-3-(trifluoromethoxy)phenyl]-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-[4-hydroxy-3-(trifluoromethoxy)phenyl]-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethoxyphenyl)-4-oxo-7-(piperazin-1-yl)-4H-quinolizine-1-carbonitrile-   2-(3-fluoro-4-methoxyphenyl)-7-[(3R)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3-fluoro-4-methoxyphenyl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(6-methoxypyridin-3-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(2,4-dimethoxyphenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(2,4-dimethoxyphenyl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethoxyphenyl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-quinolizin-4-one-   2-(5-fluoropyridin-3-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(5-fluoropyridin-3-yl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(5-chloropyridin-3-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(5-chloropyridin-3-yl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(5-chloro-6-methoxypyridin-3-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(1H-indol-6-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(1H-indol-5-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-[3-(difluoromethoxy)-4-methoxyphenyl]-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-[3-(difluoromethoxy)-4-hydroxyphenyl]-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-[3-(difluoromethoxy)-4-methoxyphenyl]-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-[3-(difluoromethoxy)-4-hydroxyphenyl]-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3-fluoro-4-methoxyphenyl)-7-(piperazin-1-yl)-4H-quinolizin-4-one-   2-(3-fluoro-4-methoxyphenyl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-quinolizin-4-one-   2-(3,5-difluorophenyl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethoxyphenyl)-7-(piperazin-1-yl)-4H-quinolizin-4-one-   2-(imidazo[1,2-a]pyridin-7-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(imidazo[1,2-a]pyridin-6-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(2-methylimidazo[1,2-a]pyridin-6-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3-chloro-4-methoxyphenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3-chloro-4-methoxyphenyl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3-ethoxy-4-methoxyphenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3-ethoxy-4-methoxyphenyl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(2-methylimidazo[1,2-a]pyridin-6-yl)-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(1,4-diazepan-1-yl)-2-(2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-(2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethoxyphenyl)-7-(2-methylpyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(piperazin-1-yl)-2-[2-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(2-ethylimidazo[1,2-a]pyridin-6-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(2,3-dimethylimidazo[1,2-a]pyridin-6-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethoxyphenyl)-7-[(3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(4-aminopiperidin-1-yl)-2-(3,4-dimethoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(1,4-diazepan-1-yl)-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(2-methyl-1,3-benzoxazol-6-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(2-methyl-1,3-benzoxazol-6-yl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(2-methyl-1,3-benzothiazol-5-yl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(2-methyl-1,3-benzothiazol-5-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(2-methyl-2H-indazol-5-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(2-methyl-2H-indazol-5-yl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3-fluoro-5-methoxyphenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3-fluoro-5-methoxyphenyl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethoxyphenyl)-9-methyl-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethoxyphenyl)-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethoxyphenyl)-7-(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3-fluoro-4,5-dimethoxyphenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethoxyphenyl)-7-(4-hydroxypiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethoxyphenyl)-7-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethoxyphenyl)-7-[4-(dimethylamino)piperidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4-methoxy-3-methylphenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   3-[4-oxo-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-2-yl]benzonitrile-   2-methoxy-5-[4-oxo-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-2-yl]benzonitrile-   2-(3-fluoro-4-hydroxyphenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4-ethoxy-3-fluorophenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-[3-fluoro-4-(2,2,2-trifluoroethoxy)phenyl]-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(2-methyl-1,3-benzoxazol-5-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(2-methyl-1,3-benzoxazol-5-yl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3-fluoro-4-methylphenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3-fluoro-4-methylphenyl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[(3S)-3-aminopyrrolidin-1-yl]-2-(3,4-dimethoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethoxyphenyl)-9-methyl-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(1,4-diazepan-1-yl)-2-(2-methyl-1,3-benzothiazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[(3S)-3-methylpiperazin-1-yl]-2-(4-methyl-1,3-thiazol-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4-methyl-1,3-thiazol-2-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethoxyphenyl)-7-(1-methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethoxyphenyl)-7-[(3S)-3-(propan-2-ylamino)pyrrolidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3-fluoro-4-methoxyphenyl)-7-(4-methyl-1,4-diazepan-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4-methoxy-3-nitrophenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-[3-fluoro-4-(methylsulfanyl)phenyl]-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(4-methyl-1,4-diazepan-1-yl)-2-(2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(2-methyl-1,3-benzoxazol-6-yl)-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-(2-methyl-1,3-benzoxazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(5-fluoro-6-methoxypyridin-3-yl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-(5-fluoro-6-methoxypyridin-3-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-(2-methyl-1,3-benzothiazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(2-methyl-1,3-benzothiazol-5-yl)-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(2-methyl-1,3-benzothiazol-5-yl)-7-(4-methyl-1,4-diazepan-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-2-(2-methyl-1,3-benzothiazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4-methyl-1H-imidazol-1-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4-methyl-1H-imidazol-1-yl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethoxyphenyl)-7-{[2-(methylamino)ethyl]amino}-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(5-fluoro-6-methoxypyridin-3-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,5-difluoro-4-methoxyphenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,5-difluoro-4-methoxyphenyl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[4-(dimethylamino)piperidin-1-yl]-2-(3-fluoro-4-methoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3-fluoro-4-methoxyphenyl)-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethoxyphenyl)-7-(piperidin-4-ylamino)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethoxyphenyl)-7-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3-chloro-5-fluorophenyl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3-chloro-5-fluorophenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[(3S)-3-methylpiperazin-1-yl]-2-(1-methyl-1H-pyrazol-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(1-methyl-1H-pyrazol-4-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(2-methyl-1,3-benzoxazol-6-yl)-7-[(3R)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(3,3-dimethylpiperazin-1-yl)-2-(2-methyl-1,3-benzoxazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(1,4-diazepan-1-yl)-2-(2-methyl-1,3-benzoxazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(2-methyl-1,3-benzoxazol-6-yl)-7-(4-methyl-1,4-diazepan-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-2-(2-methyl-1,3-benzoxazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-2-(2-methyl-1,3-benzoxazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4,5-dimethoxypyridin-2-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[3-(dimethylamino)pyrrolidin-1-yl]-2-(3-fluoro-4-methoxyphenyl)-4H-quinolizin-4-one-   7-(4-aminopiperidin-1-yl)-2-(3-fluoro-4-methoxyphenyl)-4H-quinolizin-4-one-   7-(4-ethylpiperazin-1-yl)-2-(2-methyl-1,3-benzoxazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[4-(dimethylamino)piperidin-1-yl]-2-(3-fluoro-4-methoxyphenyl)-4H-quinolizin-4-one-   2-(3-fluoro-4-methoxyphenyl)-7-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-2-(3-fluoro-4-methoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[(3R,4R)-3-(dimethylamino)-4-hydroxypyrrolidin-1-yl]-2-(3-fluoro-4-methoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(4-aminopiperidin-1-yl)-2-(3-fluoro-4-methoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3-fluoro-4-methoxyphenyl)-7-[4-(methylamino)piperidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(4-methyl-1,4-diazepan-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3-fluoro-4-methoxyphenyl)-7-[(3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3-fluoro-4-methoxyphenyl)-7-[(3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethoxyphenyl)-7-[1-(2-hydroxyethyl)piperidin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4-fluoro-3-methoxyphenyl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4-fluoro-3-methoxyphenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-difluoro-5-methoxyphenyl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-difluoro-5-methoxyphenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(2-methyl-1,3-benzothiazol-6-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(3-fluoro-4-methoxyphenyl)-2-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(2-methyl-1,3-benzothiazol-6-yl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3-fluoro-4-methoxyphenyl)-7-[(3S)-3-(methylamino)pyrrolidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3-fluoro-4-methoxyphenyl)-7-{4-[(methylamino)methyl]piperidin-1-yl}-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[(3S)-3-aminopyrrolidin-1-yl]-2-(3-fluoro-4-methoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3-fluoro-4-methoxyphenyl)-7-{[(3R)-1-methylpyrrolidin-3-yl]amino}-4H-pyrido[1,2-a]pyrimidin-4-one-   7-{4-[(dimethylamino)methyl]piperidin-1-yl}-2-(3-fluoro-4-methoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(6-methoxypyridin-2-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(piperazin-1-yl)-2-(pyridin-3-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(5-methoxypyridin-3-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   3-fluoro-5-{7-[(3S)-3-methylpiperazin-1-yl]-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl}benzonitrile-   3-fluoro-5-[4-oxo-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-2-yl]benzonitrile-   2-(3-fluoro-4-methoxyphenyl)-7-[(3′S,4′S)-4′-hydroxy-1,3′-bipyrrolidin-1′-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3-fluoro-4-methoxyphenyl)-7-{methyl[(3R)-pyrrolidin-3-yl]amino}-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[(3S)-3,4-dimethylpiperazin-1-yl]-2-(2-methyl-1,3-benzoxazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethoxyphenyl)-7-[(1-methylpiperidin-4-yl)oxy]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethoxyphenyl)-7-[(3S)-pyrrolidin-3-yloxy]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethoxyphenyl)-7-(piperidin-4-yloxy)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(1,4-diazepan-1-yl)-2-(3,4-dimethoxyphenyl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3-fluoro-4-methoxyphenyl)-7-{methyl[(3R)-1-methylpyrrolidin-3-yl]amino}-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[4-(dimethylamino)piperidin-1-yl]-2-(2-methyl-1,3-benzoxazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-2-(2-methyl-1,3-benzoxazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(4-aminopiperidin-1-yl)-2-(2-methyl-1,3-benzoxazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[(3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-2-(2-methyl-1,3-benzoxazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[(3R)-3,4-dimethylpiperazin-1-yl]-2-(2-methyl-1,3-benzoxazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethoxyphenyl)-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-quinolizin-4-one-   2-(3-fluoro-4-methoxyphenyl)-7-[(3aR,6aR)-1-methylhexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethoxyphenyl)-9-methyl-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethoxyphenyl)-7-[1-(2-hydroxyethyl)-1,2,3,6-tetrahydropyridin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethoxyphenyl)-7-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-quinolizin-4-one-   2-(3,4-dimethoxyphenyl)-9-methyl-7-(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethoxyphenyl)-9-methyl-7-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethoxyphenyl)-9-methyl-7-(1-methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(1,4-diazepan-1-yl)-2-(2-methyl-1,3-benzothiazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(2-methyl-1,3-benzothiazol-6-yl)-7-(4-methyl-1,4-diazepan-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-2-(2-methyl-1,3-benzothiazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(2-methyl-1,3-benzothiazol-6-yl)-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethoxyphenyl)-7-[(3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[(3S)-3,4-dimethylpiperazin-1-yl]-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethoxyphenyl)-9-methyl-7-[(3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethoxyphenyl)-7-[4-(dimethylamino)piperidin-1-yl]-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[(1R,5S)-8-azabicyclo[3.2.1]oct-2-en-3-yl]-2-(3,4-dimethoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethoxyphenyl)-7-(1,2,5,6-tetrahydropyridin-3-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]-2-(2-methyl-1,3-benzoxazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(2-ethyl-1,3-benzoxazol-6-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(2-ethyl-1,3-benzoxazol-6-yl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(2-methyl-1,3-benzoxazol-6-yl)-7-[(3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-2-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(3R)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(4-aminopiperidin-1-yl)-2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]-2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4-aminopiperidin-1-yl)-7-(3-fluoro-4-methoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]-7-(3-fluoro-4-methoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-7-(3-fluoro-4-methoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3-fluoro-4-methoxyphenyl)-7-[(3aR,6aS)-5-(2-hydroxyethyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3-fluoro-4-methoxyphenyl)-7-[(3aS,6aS)-1-methylhexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3-fluoro-4-methoxyphenyl)-7-[(3aR,6aS)-5-(propan-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]-2-(3-fluoro-4-methoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(3,3-dimethylpiperazin-1-yl)-2-(2-methyl-1,3-benzothiazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-2-(2-methyl-1,3-benzothiazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[4-(dimethylamino)piperidin-1-yl]-2-(2-methyl-1,3-benzothiazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(2-methyl-1,3-benzothiazol-6-yl)-7-(piperidin-4-yloxy)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(4-methyl-1,4-diazepan-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(3R)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(3-fluoro-4-methoxyphenyl)-2-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[(3S)-3,4-dimethylpiperazin-1-yl]-2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[(3R)-3,4-dimethylpiperazin-1-yl]-2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[4-(dimethylamino)piperidin-1-yl]-2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-[4-(dimethylamino)piperidin-1-yl]-7-(3-fluoro-4-methoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4-fluoro-2-methyl-1,3-benzoxazol-6-yl)-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4-fluoro-2-methyl-1,3-benzoxazol-6-yl)-7-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3-fluoro-4-methoxyphenyl)-7-[(4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(2-methyl-1,3-benzoxazol-6-yl)-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(2-methyl-1,3-benzoxazol-6-yl)-7-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(2-methyl-1,3-benzoxazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4-fluoro-2-methyl-1,3-benzoxazol-6-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4-fluoro-2-methyl-1,3-benzoxazol-6-yl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[(3S)-3,4-dimethylpiperazin-1-yl]-2-(4-fluoro-2-methyl-1,3-benzoxazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4-fluoro-2-methyl-1,3-benzoxazol-6-yl)-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(4-ethylpiperazin-1-yl)-2-(4-fluoro-2-methyl-1,3-benzoxazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4-fluoro-2-methyl-1,3-benzoxazol-6-yl)-7-(4-propylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[(3aR,6aS)-5-ethylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-2-(3-fluoro-4-methoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3-fluoro-4-methoxyphenyl)-9-methyl-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3-fluoro-4-methoxyphenyl)-7-[(4aR,7aR)-1-methyloctahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethoxyphenyl)-9-methyl-7-[(3R)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3-fluoro-4-methoxyphenyl)-9-methyl-7-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(3-fluoro-4-methoxyphenyl)-2-(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(3-fluoro-4-methoxyphenyl)-2-(1-methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(4-fluoro-2-methyl-1,3-benzoxazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4-fluoro-2-methyl-1,3-benzoxazol-6-yl)-7-(1-propyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethoxyphenyl)-7-[(1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethoxyphenyl)-7-[(2R)-2-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(2-methyl-1,3-benzoxazol-6-yl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-quinolizin-4-one-   2-(2-methyl-1,3-benzoxazol-6-yl)-7-(4-methylpiperazin-1-yl)-4H-quinolizin-4-one-   7-[(3S)-4-ethyl-3-methylpiperazin-1-yl]-2-(2-methyl-1,3-benzoxazol-6-yl)-4H-quinolizin-4-one-   7-[(3S)-3,4-dimethylpiperazin-1-yl]-2-(2-methyl-1,3-benzoxazol-6-yl)-4H-quinolizin-4-one-   7-(4-aminopiperidin-1-yl)-2-(2-methyl-1,3-benzoxazol-6-yl)-4H-quinolizin-4-one-   2-(3-fluoro-4-methoxyphenyl)-9-methyl-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[4-(dimethylamino)piperidin-1-yl]-2-(3-fluoro-4-methoxyphenyl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3-fluoro-4-methoxyphenyl)-9-methyl-7-(1-methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[4-(cyclopropylamino)piperidin-1-yl]-2-(3,4-dimethoxyphenyl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(3S)-3,4-dimethylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethoxyphenyl)-7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethoxyphenyl)-7-[(3R)-3,4-dimethylpiperazin-1-yl]-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(4-methyl-1,4-diazepan-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(3R)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(4-ethylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[4-(dimethylamino)piperidin-1-yl]-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(3,3-dimethylpiperazin-1-yl)-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(4-cyclopropylpiperazin-1-yl)-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(3R)-4-ethyl-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethoxyphenyl)-9-methyl-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethoxyphenyl)-7-[4-(dimethylamino)piperidin-1-yl]-9-ethyl-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethoxyphenyl)-7-[1-(2-hydroxyethyl)-1,2,3,6-tetrahydropyridin-4-yl]-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[4-(dimethylamino)piperidin-1-yl]-2-(2-methyl-1,3-benzothiazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(4-aminopiperidin-1-yl)-2-(2-methyl-1,3-benzothiazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[(3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-2-(2-methyl-1,3-benzothiazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1-propyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethoxyphenyl)-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrimido[1,2-a]pyrimidin-4-one-   7-(1-cyclopropyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[1-(propan-2-yl)-1,2,3,6-tetrahydropyridin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(1-cyclobutyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[1-(oxetan-3-yl)-1,2,3,6-tetrahydropyridin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethoxyphenyl)-9-methyl-7-[4-(methylamino)piperidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethoxyphenyl)-7-[4-(ethylamino)piperidin-1-yl]-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethoxyphenyl)-8-methyl-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethoxyphenyl)-7-[4-(propan-2-ylamino)piperidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(1-cyclobutyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(3,4-dimethoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethoxyphenyl)-7-[1-(propan-2-yl)-1,2,3,6-tetrahydropyridin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethoxyphenyl)-7-[1-(oxetan-3-yl)-1,2,3,6-tetrahydropyridin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethoxyphenyl)-7-(1-propyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethoxyphenyl)-7-[4-(methylamino)cyclohex-1-en-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethoxyphenyl)-7-[4-(dimethylamino)cyclohex-1-en-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethoxyphenyl)-7-{4-[ethyl(methyl)amino]cyclohex-1-en-1-yl}-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethoxyphenyl)-7-{4-[methyl(propyl)amino]cyclohex-1-en-1-yl}-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethoxyphenyl)-7-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(3,4-dimethoxyphenyl)-2-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-2-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[4-(propan-2-yl)piperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[4-(propan-2-yl)piperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(2-methylimidazo[1,2-a]pyridin-6-yl)-2-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(2-methylimidazo[1,2-a]pyridin-6-yl)-2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(3,4-dimethoxyphenyl)-2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethoxyphenyl)-9-methyl-7-(1-propyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(1-cyclobutyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(3,4-dimethoxyphenyl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(2-methyl-1,3-benzothiazol-6-yl)-7-(piperidin-4-yl)-4H-pyrimido[1,2-b]pyridazin-4-one-   7-(4-aminopiperidin-1-yl)-2-(2-methyl-1,3-benzothiazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(3-aminopyrrolidin-1-yl)-2-(2-methyl-1,3-benzothiazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]-2-(2-methyl-1,3-benzothiazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(2-methyl-1,3-benzothiazol-6-yl)-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[4-(2-methoxyethyl)piperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethoxyphenyl)-9-methyl-7-[1-(oxetan-3-yl)-1,2,3,6-tetrahydropyridin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethoxyphenyl)-9-methyl-7-[1-(propan-2-yl)-1,2,3,6-tetrahydropyridin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethoxyphenyl)-7-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethoxyphenyl)-8-methyl-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(1-cyclopropyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(3,4-dimethoxyphenyl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethoxyphenyl)-8-methyl-7-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(2-methyl-1,3-benzothiazol-6-yl)-7-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[1-(2-hydroxyethyl)-1,2,3,6-tetrahydropyridin-4-yl]-2-(2-methyl-1,3-benzothiazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(2-methyl-1,3-benzothiazol-6-yl)-7-[1-(propan-2-yl)-1,2,3,6-tetrahydropyridin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(1-cyclopropyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(2-methyl-1,3-benzothiazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(2-methyl-1,3-benzothiazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[(3R)-3,4-dimethylpiperazin-1-yl]-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethoxyphenyl)-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrimido[1,2-b]pyridazin-4-one-   7-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(1S,4S)-5-ethyl-2,5-diazabicyclo[2.2.1]hept-2-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethoxyphenyl)-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one-   2-(3-fluoro-4-methoxyphenyl)-7-(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethoxyphenyl)-7-(1-ethylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethoxyphenyl)-7-[cis-4-(methylamino)cyclohexyl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethoxyphenyl)-7-(piperidin-3-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethoxyphenyl)-9-methyl-7-[4-(propylamino)piperidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethoxyphenyl)-9-ethyl-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(2-methylimidazo[1,2-a]pyridin-6-yl)-2-(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-2-(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(4-cyclopropylpiperazin-1-yl)-2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one-   2-(3,4-dimethoxyphenyl)-7-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethoxyphenyl)-9-ethyl-7-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethoxyphenyl)-9-methyl-7-[4-(propan-2-ylamino)piperidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethoxyphenyl)-7-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethoxyphenyl)-9-ethyl-7-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethoxyphenyl)-9-methyl-7-[4-(morpholin-4-yl)piperidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(2-methyl-1,3-benzoxazol-6-yl)-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one    hydrochloride (1:1)-   2-(2-methyl-1,3-benzoxazol-6-yl)-7-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one-   7-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(2-methyl-1,3-benzoxazol-6-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one-   2-(2-methyl-1,3-benzothiazol-6-yl)-7-(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[4-(pyrrolidin-1-yl)piperidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(1,4′-bipiperidin-1′-yl)-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[4-(morpholin-4-yl)piperidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(2-methylimidazo[1,2-a]pyridin-6-yl)-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(2-methylimidazo[1,2-a]pyridin-6-yl)-7-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[4-(dimethylamino)piperidin-1-yl]-2-(2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethoxyphenyl)-7-{4-[(2-hydroxyethyl)amino]piperidin-1-yl}-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethoxyphenyl)-9-ethyl-7-(1-methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[4-(diethylamino)piperidin-1-yl]-2-(3,4-dimethoxyphenyl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethoxyphenyl)-9-ethyl-7-(1-ethylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(2-methylimidazo[1,2-a]pyridin-6-yl)-7-[4-(pyrrolidin-1-yl)piperidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(2-methylimidazo[1,2-a]pyridin-6-yl)-7-(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(2-methyl-1,3-benzothiazol-6-yl)-7-(1-methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(4-methylpiperazin-1-yl)-2-(6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[(3S)-3-methylpiperazin-1-yl]-2-(6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-(6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(1-methyl-1H-indazol-5-yl)-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-[6-(dimethylamino)pyridin-3-yl]-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[4-(diethylamino)piperidin-1-yl]-2-(2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethoxyphenyl)-7-{4-[(2-hydroxyethyl)(methyl)amino]piperidin-1-yl}-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethoxyphenyl)-9-ethyl-7-[(3R)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(2-methylimidazo[1,2-a]pyridin-6-yl)-7-(1-methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(1-methyl-1H-indazol-5-yl)-7-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-[6-(dimethylamino)pyridin-3-yl]-7-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[4-(diethylamino)piperidin-1-yl]-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1-methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1-ethylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethoxyphenyl)-9-ethyl-7-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethoxyphenyl)-7-{4-[(2-methoxyethyl)amino]piperidin-1-yl}-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[4-(dimethylamino)piperidin-1-yl]-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(2-methylimidazo[1,2-a]pyridin-6-yl)-2-(1-methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(2-methylimidazo[1,2-a]pyridin-6-yl)-2-[1-(propan-2-yl)piperidin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-2-(1-methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(1-methyl-1H-indazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(1-methyl-1H-indazol-5-yl)-7-(1-propyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-[6-(dimethylamino)pyridin-3-yl]-7-(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(4-ethylpiperazin-1-yl)-2-(6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-2-(6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[4-(dimethylamino)piperidin-1-yl]-2-(6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[4-(2-hydroxyethyl)piperazin-1-yl]-2-(6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(2-methylimidazo[1,2-a]pyridin-6-yl)-7-(1-propylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[1-(2-hydroxyethyl)-1,2,3,6-tetrahydropyridin-4-yl]-2-(1-methyl-1H-indazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[(3R)-3-methylpiperazin-1-yl]-2-(6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(2-methyl-2H-indazol-5-yl)-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(1-methyl-1H-indazol-5-yl)-7-(1-methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(2-methyl-2H-indazol-5-yl)-7-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(2-methyl-2H-indazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(1-ethylpiperidin-4-yl)-2-(2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-7-[1-(propan-2-yl)-1,2,3,6-tetrahydropyridin-4-yl]-4H-pyrazino[1,2-a]pyrimidin-4-one-   2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-7-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(1-cyclopropyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(5,7-dimethylfuro[2,3-c]pyridin-2-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(5,7-dimethylfuro[2,3-c]pyridin-2-yl)-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(5,7-dimethylfuro[2,3-c]pyridin-2-yl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(1-methyl-1H-indazol-5-yl)-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(1-methyl-1H-indazol-5-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[4-(dimethylamino)piperidin-1-yl]-2-(1-methyl-1H-indazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(4-methyl-1,4-diazepan-1-yl)-2-(1-methyl-1H-indazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(2-methyl-1,3-benzoxazol-6-yl)-4H-pyrimido[1,2-b]pyridazin-4-one-   2-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(4-ethylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(3R)-4-ethyl-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(3S)-4-ethyl-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(3R)-3-methyl-4-(propan-2-yl)piperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(3S)-3-methyl-4-(propan-2-yl)piperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(2-methyl-1,3-benzoxazol-6-yl)-7-(piperidin-4-yl)-4H-pyrimido[1,2-b]pyridazin-4-one-   2-(2-methyl-1,3-benzoxazol-6-yl)-7-(1-methylpiperidin-4-yl)-4H-pyrimido[1,2-b]pyridazin-4-one-   7-(1-ethylpiperidin-4-yl)-2-(2-methyl-1,3-benzoxazol-6-yl)-4H-pyrimido[1,2-b]pyridazin-4-one-   2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(piperidin-4-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one-   2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1-methylpiperidin-4-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one-   2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1-ethylpiperidin-4-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one-   2-(1-methyl-1H-indazol-5-yl)-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one-   2-(1-methyl-1H-indazol-5-yl)-7-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one-   7-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(1-methyl-1H-indazol-5-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one-   2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(4-ethylpiperazin-1-yl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-7-[(3R)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[(3R)-3,4-dimethylpiperazin-1-yl]-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(3R)-4-ethyl-3-methylpiperazin-1-yl]-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(piperidin-4-yl)-4H-pyrimido[1,2-b]pyridazin-4-one-   2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1-methylpiperidin-4-yl)-4H-pyrimido[1,2-b]pyridazin-4-one-   2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1-ethylpiperidin-4-yl)-4H-pyrimido[1,2-b]pyridazin-4-one-   2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(octahydro-5H-pyrrolo[3,2-c]pyridin-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(1-methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(1-ethylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[1-(propan-2-yl)piperidin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-7-(4-methyl-1,4-diazepan-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(2-methyl-2H-indazol-5-yl)-7-(piperidin-4-yl)-4H-pyrimido[1,2-b]pyridazin-4-one-   2-(2-methyl-2H-indazol-5-yl)-7-(1-methylpiperidin-4-yl)-4H-pyrimido[1,2-b]pyridazin-4-one-   7-(1-ethylpiperidin-4-yl)-2-(2-methyl-2H-indazol-5-yl)-4H-pyrimido[1,2-b]pyridazin-4-one-   2-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(1-methylpiperidin-4-yl)-4H-pyrimido[1,2-b]pyridazin-4-one-   2-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(1-ethylpiperidin-4-yl)-4H-pyrimido[1,2-b]pyridazin-4-one-   2-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[1-(2-hydroxyethyl)piperidin-4-yl]-4H-pyrimido[1,2-b]pyridazin-4-one-   2-(5,7-dimethylfuro[2,3-c]pyridin-2-yl)-7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[4-(dimethylamino)piperidin-1-yl]-2-(5,7-dimethylfuro[2,3-c]pyridin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(5,7-dimethylfuro[2,3-c]pyridin-2-yl)-7-[4-(2-hydroxyethyl)piperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[1-(2-hydroxyethyl)piperidin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[4-(2-hydroxyethyl)piperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(3R)-4-(2-hydroxyethyl)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(3S)-4-(2-methoxyethyl)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-{(3S)-4-[2-(2-hydroxyethoxy)ethyl]-3-methylpiperazin-1-yl}-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(3S)-4-cyclopropyl-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(3S)-4-cyclobutyl-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(3S)-4-(2-hydroxyethyl)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(3S)-4-(2-methoxyethyl)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(3S)-4-(2-hydroxyethyl)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-{(3S)-4-[2-(2-hydroxyethoxy)ethyl]-3-methylpiperazin-1-yl}-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(3S)-3-methyl-4-(propan-2-yl)piperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[(3S)-4-cyclopropyl-3-methylpiperazin-1-yl]-2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[(3S)-4-cyclobutyl-3-methylpiperazin-1-yl]-2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(3,3-dimethylpiperazin-1-yl)-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(1-methyl-1H-indazol-5-yl)-7-[(3R)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-(4-ethylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-[4-(2-hydroxyethyl)piperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[4-(dimethylamino)piperidin-1-yl]-2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[4-(diethylamino)piperidin-1-yl]-2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-(1-methyl-1H-indazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(1-methyl-1H-indazol-5-yl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(2-methylimidazo[1,2-a]pyridin-6-yl)-7-[1-(propan-2-yl)piperidin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(2-methylimidazo[1,2-a]pyridin-7-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(2-methylimidazo[1,2-a]pyridin-7-yl)-7-(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(2-methylimidazo[1,2-a]pyridin-7-yl)-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(4-ethylpiperazin-1-yl)-2-(2-methylimidazo[1,2-a]pyridin-7-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(2-methylimidazo[1,2-a]pyridin-7-yl)-7-(1-methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(1-ethylpiperidin-4-yl)-2-(2-methylimidazo[1,2-a]pyridin-7-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[(3S)-3,4-dimethylpiperazin-1-yl]-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-7-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(2-methylimidazo[1,2-a]pyridin-6-yl)-7-[1-(propan-2-yl)-1,2,3,6-tetrahydropyridin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(2-methyl-2H-indazol-5-yl)-7-(piperidin-4-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one-   2-(2-methyl-2H-indazol-5-yl)-7-(1-methylpiperidin-4-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one-   7-(1-ethylpiperidin-4-yl)-2-(2-methyl-2H-indazol-5-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one-   7-[1-(2-hydroxyethyl)piperidin-4-yl]-2-(2-methyl-2H-indazol-5-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one-   7-{4-[(dimethylamino)methyl]piperidin-1-yl}-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[4-(pyrrolidin-1-ylmethyl)piperidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[4-(piperidin-1-ylmethyl)piperidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethoxyphenyl)-7-{4-[(dimethylamino)methyl]piperidin-1-yl}-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethoxyphenyl)-7-[4-(pyrrolidin-1-ylmethyl)piperidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(3,4-dimethoxyphenyl)-7-[4-(piperidin-1-ylmethyl)piperidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[1-(2-hydroxyethyl)piperidin-4-yl]-2-(2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[1-(2-hydroxyethyl)-1,2,3,6-tetrahydropyridin-4-yl]-2-(2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(2-methyl-2H-indazol-5-yl)-7-(1-methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(2-methylimidazo[1,2-a]pyridin-6-yl)-7-(1-methylpiperidin-4-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one-   7-(1-ethylpiperidin-4-yl)-2-(2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one-   7-[1-(2-hydroxyethyl)piperidin-4-yl]-2-(2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one-   2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-{4-[(2-hydroxyethyl)(methyl)amino]piperidin-1-yl}-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-7-[4-(propylamino)piperidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(4-amino-4-methylpiperidin-1-yl)-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(2-methylimidazo[1,2-a]pyridin-6-yl)-7-(piperidin-4-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one-   2-(2-methyl-2H-indazol-5-yl)-7-(piperazin-1-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one-   2-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(piperidin-4-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one-   2-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-7-(piperidin-4-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one-   2-(2-methyl-2H-indazol-5-yl)-7-(4-methylpiperazin-1-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one-   7-(4-ethylpiperazin-1-yl)-2-(2-methyl-2H-indazol-5-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one-   7-[4-(2-hydroxyethyl)piperazin-1-yl]-2-(2-methyl-2H-indazol-5-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one-   2-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-7-(1-methylpiperidin-4-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one-   2-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-7-(1-ethylpiperidin-4-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one-   2-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-7-[1-(2-hydroxyethyl)piperidin-4-yl]-4H-pyrazino[1,2-a]pyrimidin-4-one-   2-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[1-(propan-2-yl)piperidin-4-yl]-4H-pyrazino[1,2-a]pyrimidin-4-one-   2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[4-(ethylamino)piperidin-1-yl]-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one-   7-{4-[bis(2-hydroxyethyl)amino]piperidin-1-yl}-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[1-(2-hydroxyethyl)piperidin-4-yl]-2-(2-methyl-1,3-benzoxazol-6-yl)-4H-pyrimido[1,2-b]pyridazin-4-one-   2-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[1-(2-hydroxyethyl)piperidin-4-yl]-4H-pyrazino[1,2-a]pyrimidin-4-one-   2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[1-(oxetan-3-yl)piperidin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(5,7-dimethylfuro[2,3-c]pyridin-2-yl)-7-(4-ethylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1-methyloctahydro-5H-pyrrolo[3,2-c]pyridin-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(1-methyl-1H-indazol-5-yl)-7-(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(1-ethylpiperidin-4-yl)-2-(1-methyl-1H-indazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[1-(2-hydroxyethyl)piperidin-4-yl]-2-(1-methyl-1H-indazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(2-methyl-2H-indazol-5-yl)-7-(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-7-(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(2-methyl-2H-indazol-5-yl)-7-[1-(propan-2-yl)piperidin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-{4-[(2-hydroxyethyl)amino]piperidin-1-yl}-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-7-[4-(methylamino)piperidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-7-[4-(propan-2-ylamino)piperidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(1-ethylpiperidin-4-yl)-2-(2-methyl-2H-indazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[1-(2-hydroxyethyl)piperidin-4-yl]-2-(2-methyl-2H-indazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-7-(1-methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-7-(1-ethylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-7-[1-(propan-2-yl)piperidin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-7-[1-(2-hydroxyethyl)piperidin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-(4-propylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-[4-(propan-2-yl)piperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(4-cyclopropylpiperazin-1-yl)-2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(4-cyclobutylpiperazin-1-yl)-2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-[4-(oxetan-3-yl)piperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1-ethyloctahydro-5H-pyrrolo[3,2-c]pyridin-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[1-(2-hydroxyethyl)octahydro-5H-pyrrolo[3,2-c]pyridin-5-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4-methoxy-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4-hydroxy-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(2-methylimidazo[1,2-a]pyridin-6-yl)-7-[1-(propan-2-yl)piperidin-4-yl]-4H-pyrazino[1,2-a]pyrimidin-4-one-   7-(1-cyclobutylpiperidin-4-yl)-2-(2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one-   7-[(3R)-3,4-dimethylpiperazin-1-yl]-2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[(3R)-4-ethyl-3-methylpiperazin-1-yl]-2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(3R)-3-methyl-4-propylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(3R)-4-(2-hydroxyethyl)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-[4-(pyrrolidin-1-yl)piperidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-(4-methyl-1,4-diazepan-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(8-ethyl-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(8-ethyl-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(3R)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(8-ethyl-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[1-(propan-2-yl)piperidin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(1-cyclopropylpiperidin-4-yl)-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(1-cyclobutylpiperidin-4-yl)-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(3R)-3-methyl-4-(propan-2-yl)piperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[(3R)-4-cyclopropyl-3-methylpiperazin-1-yl]-2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[(3R)-4-cyclobutyl-3-methylpiperazin-1-yl]-2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(3R)-3-methyl-4-(oxetan-3-yl)piperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(8-ethyl-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[4-(2-hydroxyethyl)piperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(4-cyclobutylpiperazin-1-yl)-2-(8-ethyl-2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(8-ethyl-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(3R)-4-(2-hydroxyethyl)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[(3R)-4-cyclobutyl-3-methylpiperazin-1-yl]-2-(8-ethyl-2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(8-ethyl-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(3S)-4-(2-hydroxyethyl)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[(3S)-4-cyclobutyl-3-methylpiperazin-1-yl]-2-(8-ethyl-2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-(piperidin-4-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one-   2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1-methylpiperidin-4-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one-   2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1-ethylpiperidin-4-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one-   2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1-methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1-ethylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-[1-(2-hydroxyethyl)piperidin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1-propylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(3R)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[1-(2-fluoroethyl)piperidin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[1-(3-fluoropropyl)piperidin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-[4-(2-fluoroethyl)piperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-[4-(3-fluoropropyl)piperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(3R)-4-(2-fluoroethyl)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(3R)-4-(3-fluoropropyl)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-[1-(2-fluoroethyl)piperidin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-[1-(3-fluoropropyl)piperidin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-{(3R)-4-[2-(2-hydroxyethoxy)ethyl]-3-methylpiperazin-1-yl}-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-7-(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-7-(1-methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(3R)-4-(2-hydroxyethyl)-3-methylpiperazin-1-yl]-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one-   2-[8-(hydroxymethyl)-2-methylimidazo[1,2-a]pyridin-6-yl]-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-(8-ethyl-2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(8-ethyl-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(4-methyl-1,4-diazepan-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-[8-(hydroxymethyl)-2-methylimidazo[1,2-a]pyridin-6-yl]-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(4-ethylpiperazin-1-yl)-2-[8-(hydroxymethyl)-2-methylimidazo[1,2-a]pyridin-6-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-[1-(propan-2-yl)piperidin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(1-cyclopropylpiperidin-4-yl)-2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(1-cyclobutylpiperidin-4-yl)-2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-[1-(oxetan-3-yl)piperidin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4-cyclopropyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4-cyclopropyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4-cyclopropyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-(4-ethylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4-cyclopropyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-[4-(2-hydroxyethyl)piperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1-propylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-[4-(dimethylamino)-6-methylpyrazolo[1,5-a]pyrazin-2-yl]-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(2-methyl-1H-benzimidazol-6-yl)-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(4-ethylpiperazin-1-yl)-2-(2-methyl-1H-benzimidazol-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-7-(piperidin-4-yl)-4H-pyrimido[1,2-b]pyridazin-4-one-   2-(2-methylimidazo[1,2-a]pyridin-6-yl)-7-(piperidin-4-yl)-4H-pyrimido[1,2-b]pyridazin-4-one-   7-[1-(2,2-dimethyl-1,3-dioxan-5-yl)piperidin-4-yl]-2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[1-(1,3-dihydroxypropan-2-yl)piperidin-4-yl]-2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(8-ethyl-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(8-ethyl-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(1-methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(8-ethyl-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(1-ethylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(8-ethyl-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[1-(2-hydroxyethyl)piperidin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[(3R)-3,4-dimethylpiperazin-1-yl]-2-(8-ethyl-2-methylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(8-ethyl-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(3R)-4-ethyl-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1-ethylpiperidin-4-yl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[1-(2-hydroxyethyl)piperidin-4-yl]-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(1-cyclobutylpiperidin-4-yl)-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one-   9-methyl-2-(2-methyl-2H-indazol-5-yl)-7-(1-methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[4-(dimethylamino)-4-methylpiperidin-1-yl]-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[4-(ethylamino)-4-methylpiperidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[4-methyl-4-(propylamino)piperidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-{4-[(2-hydroxyethyl)amino]-4-methylpiperidin-1-yl}-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(1-cyclobutylpiperidin-4-yl)-9-methyl-2-(2-methyl-2H-indazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[1-(2-hydroxyethyl)piperidin-4-yl]-9-methyl-2-(2-methyl-2H-indazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-7-(1-propylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-7-[(3R)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(8-cyclopropyl-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(8-cyclopropyl-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(3R)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(8-cyclopropyl-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(8-cyclopropyl-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(1-cyclopropylpiperidin-4-yl)-9-methyl-2-(2-methyl-2H-indazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(1-ethylpiperidin-4-yl)-9-methyl-2-(2-methyl-2H-indazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   9-methyl-2-(2-methyl-2H-indazol-5-yl)-7-(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(1-methylpiperidin-4-yl)oxy]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(6-methyl-4-propylpyrazolo[1,5-a]pyrazin-2-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(4-methylpiperazin-1-yl)-2-(6-methyl-4-propylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(4-ethylpiperazin-1-yl)-2-(6-methyl-4-propylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[4-(2-hydroxyethyl)piperazin-1-yl]-2-(6-methyl-4-propylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[(3R)-3-methylpiperazin-1-yl]-2-(6-methyl-4-propylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[(3S)-3-methylpiperazin-1-yl]-2-(6-methyl-4-propylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-(6-methyl-4-propylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-7-[(3R)-3-methyl-4-(propan-2-yl)piperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(4-amino-4-methylpiperidin-1-yl)-2-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(3S)-3-ethylpiperazin-1-yl]-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one-   2-[2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl]-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[(3R)-3-methylpiperazin-1-yl]-2-[2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[(3S)-3-methylpiperazin-1-yl]-2-[2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-[2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(4-amino-4-methylpiperidin-1-yl)-2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(2,7-dimethyl-2H-indazol-5-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(2,7-dimethyl-2H-indazol-5-yl)-7-(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(3-aminoprop-1-yn-1-yl)-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(2,7-dimethyl-2H-indazol-5-yl)-7-[(3R)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(3-aminopropyl)-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-(1-ethyl-3-methylpyrrolo[1,2-a]pyrazin-7-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(1,4-diazepan-1-yl)-2-(1-ethyl-3-methylpyrrolo[1,2-a]pyrazin-7-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(2,7-dimethyl-2H-indazol-5-yl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(2,7-dimethyl-2H-indazol-5-yl)-7-[(3S)-3,4-dimethylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(2,7-dimethyl-2H-indazol-5-yl)-7-(1-methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(2,7-dimethyl-2H-indazol-5-yl)-7-(1-ethylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   9-methyl-2-(2-methyl-2H-indazol-5-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   9-methyl-2-(2-methyl-2H-indazol-5-yl)-7-[(3R)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   9-methyl-2-(2-methyl-2H-indazol-5-yl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[3-(dimethylamino)azetidin-1-yl]-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[3-(diethylamino)azetidin-1-yl]-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[3-(pyrrolidin-1-yl)azetidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(1,4-diazepan-1-yl)-2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[(3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-2-(6-methyl-4-propylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(6-methyl-4-propylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[(3S)-3-(aminomethyl)pyrrolidin-1-yl]-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[3-(piperidin-1-yl)azetidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(6-methyl-4-propylpyrazolo[1,5-a]pyrazin-2-yl)-7-(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(2,7-diazaspiro[4.4]non-2-yl)-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(2,7-dimethyl-2H-indazol-5-yl)-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[3-(dimethylamino)propyl]-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-{(3S)-3-[(dimethylamino)methyl]pyrrolidin-1-yl}-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-7-(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   9-methyl-2-(1-methyl-1H-indazol-5-yl)-7-(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-7-(1-methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(1,7-dimethyl-1H-indazol-5-yl)-7-(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(1,7-dimethyl-1H-indazol-5-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(1,7-dimethyl-1H-indazol-5-yl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   7-{(3S)-3-[(diethylamino)methyl]pyrrolidin-1-yl}-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-{(3S)-3-[(ethylamino)methyl]pyrrolidin-1-yl}-4H-pyrido[1,2-a]pyrimidin-4-one-   7-{3-[(dimethylamino)methyl]azetidin-1-yl}-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-{3-[(diethylamino)methyl]azetidin-1-yl}-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(1-ethyl-3-methylpyrrolo[1,2-a]pyrazin-7-yl)-7-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-7-[(3R)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   9-methyl-2-(1-methyl-1H-indazol-5-yl)-7-(1-methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[(3R)-3,4-dimethylpiperazin-1-yl]-2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(1-ethylpiperidin-4-yl)-9-methyl-2-(1-methyl-1H-indazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[1-(2-hydroxyethyl)piperidin-4-yl]-9-methyl-2-(1-methyl-1H-indazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[(3S)-3,4-dimethylpiperazin-1-yl]-2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1-ethylpiperidin-4-yl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one-   9-methyl-2-(2-methyl-2H-indazol-5-yl)-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one-   7-(1-cyclobutylpiperidin-4-yl)-2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-[1-(2-hydroxyethyl)piperidin-4-yl]-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(8-ethyl-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(8-ethyl-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   9-methyl-2-(2-methyl-2H-indazol-5-yl)-7-(piperidin-4-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one-   7-[(3R)-3-(aminomethyl)pyrrolidin-1-yl]-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(2S,6S)-2,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   7-{(3R)-3-[(dimethylamino)methyl]pyrrolidin-1-yl}-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[(2S,6S)-2,6-dimethylpiperidin-4-yl]-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[4-(2-hydroxyethyl)piperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(imidazo[1,2-a]pyridin-6-yl)-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4-fluoro-2-methyl-1,3-benzoxazol-6-yl)-7-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(2,7-diazaspiro[3.5]non-7-yl)-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(4-methylpiperazin-1-yl)-2-(2-methyl[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(4-methylpiperazin-1-yl)-2-[2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-methyl-6-[7-(4-methylpiperazin-1-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl]imidazo[1,2-a]pyridine-8-carbonitrile-   2-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-(4,7-diazaspiro[2.5]oct-7-yl)-2-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(1-methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(4-hydroxypiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]-2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(8aS)-8a-methylhexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-(4-ethylpiperazin-1-yl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-7-(4-ethylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-7-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-7-(8a-methylhexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]-2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-{[2-(morpholin-4-yl)ethyl]amino}-4H-pyrido[1,2-a]pyrimidin-4-one-   7-{[2-(dimethylamino)ethyl]amino}-2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-{[2-(dimethylamino)ethyl](methyl)amino}-2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-{methyl[2-(methylamino)ethyl]amino}-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]-2-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-2-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[2-(dimethylamino)ethoxy]-2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[2-(dimethylamino)ethoxy]-2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-(piperidin-4-ylmethoxy)-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-[2-(piperidin-1-yl)ethoxy]-4H-pyrido[1,2-a]pyrimidin-4-one-   2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-[3-(morpholin-4-yl)propoxy]-4H-pyrido[1,2-a]pyrimidin-4-one-   7-[3-(dimethylamino)propoxy]-2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,    or-   2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-[(3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one

or a salt, isotopologue, stereoisomer, racemate, enantiomer,diastereomer or tautomer thereof.

In another embodiment, the compound of Formula (I) used in a methoddisclosed herein is a compound selected from the group consisting of:

-   2-(3,5-difluoro-4-hydroxyphenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one    hydrochloride-   7-[4-(dimethylamino)piperidin-1-yl]-2-(3-fluoro-4-methoxyphenyl)-4H-quinolizin-4-one    acetate-   2-(2-methyl-1,3-benzothiazol-6-yl)-7-(piperidin-4-yl)-4H-pyrimido[1,2-b]pyridazin-4-one    trifluoroacetate (1:1), or-   2-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one    hydrochloride (1:2)

or a free base, isotopologue, stereoisomer, racemate, enantiomer,diastereomer or tautomer thereof.

Compounds of Formula (I) can be prepared using reagents and methodsknown in the art, including the methods provided in InternationalApplication No. PCT/US2013/025292, filed on Feb. 8, 2013, and publishedas International Publication No. WO 2013/119916 on Aug. 15, 2013, theentire contents which are incorporated herein by reference (see inparticular, General Synthetic Methods, Schemes A-J, at paragraphs[001126] to [001159]; and Specific Synthetic Examples, at paragraphs[001160] to [001573] and Table 1).

Terminology

The chemical terms used above and throughout the description herein,unless specifically defined otherwise, shall be understood by one ofordinary skill in the art to have the following indicated meanings.

As used herein, the term “C₁₋₈alkyl” generally refers to saturatedhydrocarbon radicals having from one to eight carbon atoms in a straightor branched chain configuration, including, but not limited to, methyl,ethyl, n-propyl (also referred to as propyl or propanyl), isopropyl,n-butyl (also referred to as butyl or butanyl), isobutyl, sec-butyl,tert-butyl, n-pentyl (also referred to as pentyl or pentanyl), n-hexyl(also referred to as hexyl or hexanyl), n-heptyl (also referred to asheptyl or heptanyl), n-octyl and the like. In some embodiments,C₁₋₈alkyl includes, but is not limited to, C₁₋₆alkyl, C₁₋₄alkyl and thelike. A C₁₋₈alkyl radical is optionally substituted with substituentspecies as described herein where allowed by available valences.

As used herein, the term “C₂₋₈alkenyl” generally refers to partiallyunsaturated hydrocarbon radicals having from two to eight carbon atomsin a straight or branched chain configuration and one or morecarbon-carbon double bonds therein, including, but not limited to,ethenyl (also referred to as vinyl), allyl, propenyl and the like. Insome embodiments, C₂₋₈alkenyl includes, but is not limited to,C₂₋₆alkenyl, C₂₋₄alkenyl and the like. A C₂₋₈alkenyl radical isoptionally substituted with substituent species as described hereinwhere allowed by available valences.

As used herein, the term “C₂₋₈alkynyl” generally refers to partiallyunsaturated hydrocarbon radicals having from two to eight carbon atomsin a straight or branched chain configuration and one or morecarbon-carbon triple bonds therein, including, but not limited to,ethynyl, propynyl, butynyl and the like. In some embodiments,C₂₋₈alkynyl includes, but is not limited to, C₂₋₆alkynyl, C₂₋₄alkynyland the like. A C₂₋₈alkynyl radical is optionally substituted withsubstituent species as described herein where allowed by availablevalences.

As used herein, the term “C₁₋₈alkoxy” generally refers to saturatedhydrocarbon radicals having from one to eight carbon atoms in a straightor branched chain configuration of the formula: —O—C₁₋₈alkyl, including,but not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy and the like. Insome embodiments, C₁₋₈alkoxy includes, but is not limited to,C₁₋₆alkoxy, C₁₋₄alkoxy and the like. A C₁₋₈alkoxy radical is optionallysubstituted with substituent species as described herein where allowedby available valences.

As used herein, the term “C₃₋₁₄cycloalkyl” generally refers to asaturated or partially unsaturated monocyclic, bicyclic or polycyclichydrocarbon radical, including, but not limited to, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl,cyclooctyl, 1H-indanyl, indenyl, tetrahydro-naphthalenyl and the like.In some embodiments, C₃₋₁₄cycloalkyl includes, but is not limited to,C₃₋₈cycloalkyl, C₅₋₈cycloalkyl, C₃₋₁₀cycloalkyl and the like. AC₃₋₁₄cycloalkyl radical is optionally substituted with substituentspecies as described herein where allowed by available valences.

As used herein, the term “aryl” generally refers to a monocyclic,bicyclic or polycyclic aromatic carbon atom ring structure radical,including, but not limited to, phenyl, naphthyl, anthracenyl, fluorenyl,azulenyl, phenanthrenyl and the like. An aryl radical is optionallysubstituted with substituent species as described herein where allowedby available valences.

As used herein, the term “heteroaryl” generally refers to a monocyclic,bicyclic or polycyclic aromatic carbon atom ring structure radical inwhich one or more carbon atom ring members have been replaced, whereallowed by structural stability, with one or more heteroatoms, such asan O, S or N atom, including, but not limited to, furanyl (also referredto as furyl), thienyl (also referred to as thiophenyl), pyrrolyl,2H-pyrrolyl, 3H-pyrrolyl, pyrazolyl, 1H-pyrazolyl, imidazolyl,1H-imidazolyl, isoxazolyl, isothiazolyl, oxazolyl, 1,3-thiazolyl,triazolyl (such as 1H-1,2,3-triazolyl and the like), oxadiazolyl (suchas 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl and the like), thiadiazolyl,tetrazolyl (such as 1H-tetrazolyl, 2H-tetrazolyl and the like),pyridinyl (also referred to as pyridyl), pyrimidinyl, pyrazinyl,pyridazinyl, triazinyl, indolyl, 1H-indolyl, indazolyl, 1H-indazolyl,2H-indazolyl, indolizinyl, isoindolyl, benzofuranyl, benzothienyl (alsoreferred to as benzothiophenyl), benzoimidazolyl, 1H-benzoimidazolyl,1,3-benzothiazolyl, 1,3-benzoxazolyl (also referred to as1,3-benzooxazolyl), purinyl, 9H-purinyl, quinolinyl, isoquinolinyl,quinazolinyl, quinoxalinyl, 1,3-diazinyl, 1,2-diazinyl, 1,2-diazolyl,1,4-diazanaphthalenyl, acridinyl, furo[3,2-b]pyridinyl,furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl, 6H-thieno[2,3-b]pyrrolyl,thieno[3,2-c]pyridinyl, thieno[2,3-d]pyrimidinyl,1H-pyrrolo[2,3-b]pyridinyl, 1H-pyrrolo[2,3-c]pyridinyl,1H-pyrrolo[3,2-b]pyridinyl, pyrrolo[1,2-a]pyrazinyl,pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridinyl,pyrazolo[1,5-a]pyrazinyl, imidazo[1,2-a]pyridinyl,3H-imidazo[4,5-b]pyridinyl, imidazo[1,2-a]pyrimidinyl,imidazo[1,2-c]pyrimidinyl, imidazo[1,2-b]pyridazinyl,imidazo[1,2-a]pyrazinyl, imidazo[2,1-b][1,3]thiazolyl,imidazo[2,1-b][1,3,4]thiadiazolyl, [1,2,4]triazolo[1,5-a]pyridinyl,[1,2,4]triazolo[4,3-a]pyridinyl and the like. A heteroaryl radical isoptionally substituted on a carbon or nitrogen atom ring member withsubstituent species as described herein where allowed by availablevalences.

As used herein, the term “heterocyclyl” generally refers to a saturatedor partially unsaturated monocyclic, bicyclic or polycyclic carbon atomring structure radical in which one or more carbon atom ring membershave been replaced, where allowed by structural stability, with aheteroatom, such as an O, S or N atom, including, but not limited to,oxiranyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolinyl,pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl,isoxazolinyl, isoxazolidinyl, isothiazolinyl, isothiazolidinyl,oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, triazolinyl,triazolidinyl, oxadiazolinyl, oxadiazolidinyl, thiadiazolinyl,thiadiazolidinyl, tetrazolinyl, tetrazolidinyl, pyranyl,dihydro-2H-pyranyl, thiopyranyl, 1,3-dioxanyl,1,2,5,6-tetrahydropyridinyl, 1,2,3,6-tetrahydropyridinyl, piperidinyl,piperazinyl, morpholinyl, thiomorpholinyl, 1,4-diazepanyl,1,3-benzodioxolyl (also referred to as benzo[d][1,3]dioxolyl),1,4-benzodioxanyl, 2,3-dihydro-1,4-benzodioxinyl (also referred to as2,3-dihydrobenzo[b][1,4]dioxinyl),hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl,(3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl,(3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl,hexahydropyrrolo[3,4-b]pyrrol-(2H)-yl,(3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-(2H)-yl,(3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-(2H)-yl,hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl,(3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl,(3aR,6aR)-hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl,octahydro-5H-pyrrolo[3,2-c]pyridinyl,octahydro-6H-pyrrolo[3,4-b]pyridinyl,(4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridinyl,(4aS,7aS)-octahydro-6H-pyrrolo[3,4-b]pyridinyl,hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl,(7R,8aS)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl,(8aS)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl,(8aR)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl,(8aS)-octahydropyrrolo[1,2-a]pyrazin-(1H)-yl,(8aR)-octahydropyrrolo[1,2-a]pyrazin-(1H)-yl,hexahydropyrrolo[1,2-a]pyrazin-(2H)-one,octahydro-2H-pyrido[1,2-a]pyrazinyl, 3-azabicyclo[3.1.0]hexyl,(1R,5S)-3-azabicyclo[3.1.0]hexyl, 8-azabicyclo[3.2.1]octyl,(1R,5S)-8-azabicyclo[3.2.1]octyl, 8-azabicyclo[3.2.1]oct-2-enyl,(1R,5S)-8-azabicyclo[3.2.1]oct-2-enyl, 9-azabicyclo[3.3.1]nonyl,(1R,5S)-9-azabicyclo[3.3.1]nonyl, 2,5-diazabicyclo[2.2.1]heptyl,(1S,4S)-2,5-diazabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.2]octyl,3,8-diazabicyclo[3.2.1]octyl, (1R,5S)-3,8-diazabicyclo[3.2.1]octyl,1,4-diazabicyclo[3.2.2]nonyl, azaspiro[3.3]heptyl,2,6-diazaspiro[3.3]heptyl, 2,7-diazaspiro[3.5]nonyl,5,8-diazaspiro[3.5]nonyl, 2,7-diazaspiro[4.4]nonyl,6,9-diazaspiro[4.5]decyl and the like. A heterocyclyl radical isoptionally substituted on a carbon or nitrogen atom ring member withsubstituent species as described herein where allowed by availablevalences.

As used herein, the term “C₁₋₈alkoxy-C₁₋₈alkyl” refers to a radical ofthe formula: —C₁₋₈alkyl-O—C₁₋₈alkyl.

As used herein, the term “C₁₋₈alkoxy-C₁₋₈alkyl-amino” refers to aradical of the formula: —NH—C₁₋₈alkyl-O—C₁₋₈alkyl.

As used herein, the term “(C₁₋₈alkoxy-C₁₋₈alkyl)₂-amino” refers to aradical of the formula: —N(C₁₋₈alkyl-O—C₁₋₈alkyl)₂.

As used herein, the term “C₁₋₈alkoxy-C₁₋₈alkyl-amino-C₁₋₈alkoxy” refersto a radical of the formula: —O—C₁₋₈alkyl-NH—C₁₋₈alkyl-O—C₁₋₈alkyl.

As used herein, the term “(C₁₋₈alkoxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkoxy”refers to a radical of the formula:—C₁₋₈alkyl-N(C₁₋₈alkyl-O—C₁₋₈alkyl)₂.

As used herein, the term“(C₁₋₈alkoxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkoxy” refers to a radicalof the formula: —C₁₋₈alkyl-N(C₁₋₈alkyl)(C₁₋₈alkyl-O—C₁₋₈alkyl).

As used herein, the term “C₁₋₈alkoxy-C₁₋₈alkyl-amino-C₁₋₈alkyl” refersto a radical of the formula: —C₁₋₈alkyl-NH—C₁₋₈alkyl-O—C₁₋₈alkyl.

As used herein, the term “(C₁₋₈alkoxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl”refers to a radical of the formula:—C₁₋₈alkyl-N(C₁₋₈alkyl-O—C₁₋₈alkyl)₂.

As used herein, the term“(C₁₋₈alkoxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl” refers to a radicalof the formula: —C₁₋₈alkyl-N(C₁₋₈alkyl)(C₁₋₈alkyl-O—C₁₋₈alkyl).

As used herein, the term “C₁₋₈alkoxy-carbonyl” refers to a radical ofthe formula: —C(O)—O—C₁₋₈alkyl.

As used herein, the term “C₁₋₈alkoxy-carbonyl-C₂₋₈alkenyl” refers to aradical of the formula: —C₂₋₈alkenyl-C(O)—O—C₁₋₈alkyl.

As used herein, the term “C₁₋₈alkoxy-carbonyl-amino” refers to a radicalof the formula: —NH—C(O)—O—C₁₋₈alkyl.

As used herein, the term “C₁₋₈alkyl-amino” refers to a radical of theformula: —NH—C₁₋₈alkyl.

As used herein, the term “(C₁₋₈alkyl)₂-amino” refers to a radical of theformula: —N(C₁₋₈alkyl)₂.

As used herein, the term “C₁₋₈alkyl-amino-C₂₋₈alkenyl” refers to aradical of the formula: —C₂₋₈alkenyl-NH—C₁₋₈alkyl.

As used herein, the term “(C₁₋₈alkyl)₂-amino-C₂₋₈alkenyl” refers to aradical of the formula: —C₂₋₈alkenyl-N(C₁₋₈alkyl)₂.

As used herein, the term “C₁₋₈alkyl-amino-C₁₋₈alkoxy” refers to aradical of the formula: —O—C₁₋₈alkyl-NH—C₁₋₈alkyl.

As used herein, the term “(C₁₋₈alkyl)₂-amino-C₁₋₈alkoxy” refers to aradical of the formula: —O—C₁₋₈alkyl-N(C₁₋₈alkyl)₂.

As used herein, the term “C₁₋₈alkyl-amino-C₁₋₈alkyl” refers to a radicalof the formula: —C₁₋₈alkyl-NH—C₁₋₈alkyl.

As used herein, the term “(C₁₋₈alkyl)₂-amino-C₁₋₈alkyl” refers to aradical of the formula: —C₁₋₈alkyl-N(C₁₋₈alkyl)₂.

As used herein, the term “C₁₋₈alkyl-amino-C₁₋₈alkyl-amino” refers to aradical of the formula: —NH—C₁₋₈alkyl-NH—C₁₋₈alkyl.

As used herein, the term “(C₁₋₈alkyl)₂-amino-C₁₋₈alkyl-amino” refers toa radical of the formula: —NH—C₁₋₈alkyl-N(C₁₋₈alkyl)₂.

As used herein, the term “(C₁₋₈alkyl-amino-C₁₋₈alkyl)₂-amino” refers toa radical of the formula: —N(C₁₋₈alkyl-NH—C₁₋₈alkyl)₂.

As used herein, the term “[(C₁₋₈alkyl)₂-amino-C₁₋₈alkyl]₂-amino” refersto a radical of the formula: —N[C₁₋₈alkyl-N(C₁₋₈alkyl)₂]₂.

As used herein, the term “(C₁₋₈alkyl-amino-C₁₋₈alkyl)(C₁₋₈alkyl)amino”refers to a radical of the formula:—N(C₁₋₈alkyl)(C₁₋₈alkyl-NH—C₁₋₈alkyl).

As used herein, the term“[(C₁₋₈alkyl)₂-amino-C₁₋₈alkyl](C₁₋₈alkyl)amino” refers to a radical ofthe formula: —N(C₁₋₈alkyl)[C₁₋₈alkyl-N(C₁₋₈alkyl)₂].

As used herein, the term “C₁₋₈alkyl-amino-C₂₋₈alkynyl” refers to aradical of the formula: —C₂₋₈alkynyl-NH—C₁₋₈alkyl.

As used herein, the term “(C₁₋₈alkyl)₂-amino-C₂₋₈alkynyl” refers to aradical of the formula: —C₂₋₈alkynyl-N(C₁₋₈alkyl)₂.

As used herein, the term “C₁₋₈alkyl-carbonyl” refers to a radical of theformula: —C(O)—C₁₋₈alkyl.

As used herein, the term “C₁₋₈alkyl-carbonyl-amino” refers to a radicalof the formula: —NH—C(O)—C₁₋₈alkyl.

As used herein, the term “C₁₋₈alkyl-thio” refers to a radical of theformula: —S—C₁₋₈alkyl.

As used herein, the term “amino-C₂₋₈alkenyl” refers to a radical of theformula: —C₂₋₈alkenyl-NH₂.

As used herein, the term “amino-C₁₋₈alkoxy” refers to a radical of theformula: —O—C₁₋₈alkyl-NH₂.

As used herein, the term “amino-C₁₋₈alkyl” refers to a radical of theformula: —C₁₋₈alkyl-NH₂.

As used herein, the term “amino-C₁₋₈alkyl-amino” refers to a radical ofthe formula: —NH—C₁₋₈alkyl-NH₂.

As used herein, the term “(amino-C₁₋₈alkyl)₂-amino” refers to a radicalof the formula: —N(C₁₋₈alkyl-NH₂)₂.

As used herein, the term “(amino-C₁₋₈alkyl)(C₁₋₈alkyl)amino” refers to aradical of the formula: —N(C₁₋₈alkyl)(C₁₋₈alkyl-NH₂).

As used herein, the term “amino-C₂₋₈alkynyl” refers to a radical of theformula: —C₂₋₈alkynyl-NH₂.

As used herein, the term “aryl-C₁₋₈alkoxy-carbonyl” refers to a radicalof the formula: —C(O)—O—C₁₋₈alkyl-aryl.

As used herein, the term “aryl-C₁₋₈alkyl” refers to a radical of theformula: —C₁₋₈alkyl-aryl.

As used herein, the term “aryl-C₁₋₈alkyl-amino” refers to a radical ofthe formula: —NH—C₁₋₈alkyl-aryl.

As used herein, the term “(aryl-C₁₋₈alkyl)₂-amino” refers to a radicalof the formula: —N(C₁₋₈alkyl-aryl)₂.

As used herein, the term “(aryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino” refers to aradical of the formula: —N(C₁₋₈alkyl)(C₁₋₈alkyl-aryl).

As used herein, the term “aryl-C₁₋₈alkyl-amino-C₁₋₈alkyl” refers to aradical of the formula: —C₁₋₈alkyl-NH—C₁₋₈alkyl-aryl.

As used herein, the term “(aryl-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl” refers to aradical of the formula: —C₁₋₈alkyl-N(C₁₋₈alkyl-aryl)₂.

As used herein, the term “(aryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl”refers to a radical of the formula:—C₁₋₈alkyl-N(C₁₋₈alkyl)(C₁₋₈alkyl-aryl).

As used herein, the term “aryl-amino” refers to a radical of theformula: —NH-aryl.

As used herein, the term “aryl-amino-carbonyl” refers to a radical ofthe formula: —C(O)—NH-aryl.

As used herein, the term “aryl-sulfonyloxy-C₁₋₈alkyl” refers to aradical of the formula: —C₁₋₈alkyl-O—SO₂-aryl.

As used herein, the term “benzoxy-carbonyl” refers to a radical of theformula: —C(O)O—CH₂-phenyl.

As used herein, the term “C₃₋₁₄cycloalkyl-C₁₋₈alkyl” refers to a radicalof the formula: —C₁₋₈alkyl-C₃₋₁₄cycloalkyl.

As used herein, the term “C₃₋₁₄cycloalkyl-amino” refers to a radical ofthe formula: —NH—C₃₋₁₄cycloalkyl.

As used herein, the term “C₃₋₁₄cycloalkyl-oxy” refers to a radical ofthe formula: —O—C₃₋₁₄cycloalkyl.

As used herein, the term “halo” or “halogen” generally refers to ahalogen atom radical, including fluoro, chloro, bromo and iodo.

As used herein, the term “halo-C₁₋₈alkoxy” refers to a radical of theformula: —O—C₁₋₈alkyl-halo, wherein C₁₋₈alkyl is partially or completelysubstituted with one or more halogen atoms where allowed by availablevalences.

As used herein, the term “halo-C₁₋₈alkyl” refers to a radical of theformula: —C₁₋₈alkyl-halo, wherein C₁₋₈alkyl is partially or completelysubstituted with one or more halogen atoms where allowed by availablevalences.

As used herein, the term “halo-C₁₋₈alkyl-amino” refers to a radical ofthe formula: —NH—C₁₋₈alkyl-halo.

As used herein, the term “(halo-C₁₋₈alkyl)(C₁₋₈alkyl)amino” refers to aradical of the formula: —N(C₁₋₈alkyl)(C₁₋₈alkyl-halo).

As used herein, the term “(halo-C₁₋₈alkyl)₂-amino” refers to a radicalof the formula: —N(C₁₋₈alkyl-halo)₂.

As used herein, the term “heteroaryl-C₁₋₈alkoxy” refers to a radical ofthe formula: —O—C₁₋₈alkyl-heteroaryl.

As used herein, the term “heteroaryl-C₁₋₈alkyl” refers to a radical ofthe formula: —C₁₋₈alkyl-heteroaryl.

As used herein, the term “heteroaryl-C₁₋₈alkyl-amino” refers to aradical of the formula: —NH—C₁₋₈alkyl-heteroaryl.

As used herein, the term “(heteroaryl-C₁₋₈alkyl)₂-amino” refers to aradical of the formula: —N(C₁₋₈alkyl-heteroaryl)₂.

As used herein, the term “(heteroaryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino” refersto a radical of the formula: —N(C₁₋₈alkyl)(C₁₋₈alkyl-heteroaryl).

As used herein, the term “heteroaryl-C₁₋₈alkyl-amino-C₁₋₈alkyl” refersto a radical of the formula: —C₁₋₈alkyl-NH—C₁₋₈alkyl-heteroaryl.

As used herein, the term “(heteroaryl-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl”refers to a radical of the formula: —C₁₋₈alkyl-N(C₁₋₈alkyl-heteroaryl)₂.

As used herein, the term“(heteroaryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl” refers to a radicalof the formula: —C₁₋₈alkyl-N(C₁₋₈alkyl)(C₁₋₈alkyl-heteroaryl).

As used herein, the term “heteroaryl-amino” refers to a radical of theformula: —NH-heteroaryl.

As used herein, the term “heterocyclyl-C₁₋₈alkoxy” refers to a radicalof the formula: —O—C₁₋₈alkyl-heterocyclyl.

As used herein, the term “heterocyclyl-C₁₋₈alkyl” refers to a radical ofthe formula: —C₁₋₈alkyl-heterocyclyl.

As used herein, the term “heterocyclyl-C₁₋₈alkyl-amino” refers to aradical of the formula: —NH—C₁₋₈alkyl-heterocyclyl.

As used herein, the term “(heterocyclyl-C₁₋₈alkyl)₂-amino” refers to aradical of the formula: —N(C₁₋₈alkyl-heterocyclyl)₂.

As used herein, the term “(heterocyclyl-C₁₋₈alkyl)(C₁₋₈alkyl)amino”refers to a radical of the formula:—N(C₁₋₈alkyl)(C₁₋₈alkyl-heterocyclyl).

As used herein, the term “heterocyclyl-C₁₋₈alkyl-amino-C₁₋₈alkyl” refersto a radical of the formula: —C₁₋₈alkyl-NH—C₁₋₈alkyl-heterocyclyl.

As used herein, the term “(heterocyclyl-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl”refers to a radical of the formula:—C₁₋₈alkyl-N(C₁₋₈alkyl-heterocyclyl)₂.

As used herein, the term“(heterocyclyl-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl” refers to a radicalof the formula: —C₁₋₈alkyl-N(C₁₋₈alkyl)(C₁₋₈alkyl-heterocyclyl).

As used herein, the term “heterocyclyl-amino” refers to a radical of theformula: —NH-heterocyclyl.

As used herein, the term “(heterocyclyl)(C₁₋₈alkyl)amino” refers to aradical of the formula: —N(C₁₋₈alkyl)(heterocyclyl).

As used herein, the term “heterocyclyl-amino-C₁₋₈alkyl” refers to aradical of the formula: —C₁₋₈alkyl-NH-heterocyclyl.

As used herein, the term “heterocyclyl-carbonyl” refers to a radical ofthe formula: —C(O)-heterocyclyl.

As used herein, the term “heterocyclyl-carbonyl-oxy” refers to a radicalof the formula: —O—C(O)-heterocyclyl.

As used herein, the term “heterocyclyl-oxy” refers to a radical of theformula: —O-heterocyclyl.

As used herein, the term “hydroxy” refers to a radical of the formula:—OH.

As used herein, the term “hydroxy-C₁₋₈alkoxy-C₁₋₈alkyl” refers to aradical of the formula: —C₁₋₈alkyl-O—C₁₋₈alkyl-OH.

As used herein, the term “hydroxy-C₁₋₈alkyl” refers to a radical of theformula: —C₁₋₈alkyl-OH, wherein C₁₋₈alkyl is partially or completelysubstituted with one or more hydroxy radicals where allowed by availablevalences.

As used herein, the term “hydroxy-C₁₋₈alkyl-amino” refers to a radicalof the formula: —NH—C₁₋₈alkyl-OH.

As used herein, the term “(hydroxy-C₁₋₈alkyl)₂-amino” refers to aradical of the formula: —N(C₁₋₈alkyl-OH)₂.

As used herein, the term “(hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino” refers toa radical of the formula: —N(C₁₋₈alkyl)(C₁₋₈alkyl-OH).

As used herein, the term “hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkyl” refers to aradical of the formula: —C₁₋₈alkyl-NH—C₁₋₈alkyl-OH.

As used herein, the term “(hydroxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl” refersto a radical of the formula: —C₁₋₈alkyl-N(C₁₋₈alkyl-OH)₂.

As used herein, the term “(hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl”refers to a radical of the formula:—C₁₋₈alkyl-N(C₁₋₈alkyl)(C₁₋₈alkyl-OH).

As used herein, the term “hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkoxy” refers toa radical of the formula: —O—C₁₋₈alkyl-NH—C₁₋₈alkyl-OH.

As used herein, the term “(hydroxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkoxy” refersto a radical of the formula: —C₁₋₈alkyl-N(C₁₋₈alkyl-OH)₂.

As used herein, the term“(hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkoxy” refers to a radical ofthe formula: —O—C₁₋₈alkyl-N(C₁₋₈alkyl)(C₁₋₈alkyl-OH).

As used herein, the term “hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkyl-amino”refers to a radical of the formula: —NH—C₁₋₈alkyl-NH—C₁₋₈alkyl-OH.

As used herein, the term “(hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkyl)₂-amino”refers to a radical of the formula: —N(C₁₋₈alkyl-NH—C₁₋₈alkyl-OH)₂.

As used herein, the term “(hydroxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl-amino”refers to a radical of the formula: —NH—C₁₋₈alkyl-N(C₁₋₈alkyl-OH)₂.

As used herein, the term“(hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkyl)(C₁₋₈alkyl)amino” refers to aradical of the formula: —N(C₁₋₈alkyl)(C₁₋₈alkyl-NH—C₁₋₈alkyl-OH).

As used herein, the term“[(hydroxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl](C₁₋₈alkyl)amino” refers to aradical of the formula: —N(C₁₋₈alkyl)[C₁₋₈alkyl-N(C₁₋₈alkyl-OH)₂].

As used herein, the term“(hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl-amino” refers to aradical of the formula: —NH—C₁₋₈alkyl-N(C₁₋₈alkyl, C₁₋₈alkyl-OH).

As used herein, the term“[(hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl](C₁₋₈alkyl)amino” refersto a radical of the formula: —N(C₁₋₈alkyl)[C₁₋₈alkyl—N(C₁₋₈alkyl)(C₁₋₈alkyl —OH)].

As used herein, the term “substituent” means positional variables on theatoms of a core molecule that are attached at a designated atomposition, replacing one or more hydrogen atoms on the designated atom,provided that the atom of attachment does not exceed the availablevalence or shared valences, such that the substitution results in astable compound. Accordingly, combinations of substituents and/orvariables are permissible only if such combinations result in stablecompounds. It should also be noted that any carbon as well as heteroatomwith a valence level that appears to be unsatisfied as described orshown herein is assumed to have a sufficient number of hydrogen atom(s)to satisfy the valences described or shown.

For the purposes of this description, where one or more substituentvariables for a compound of Formula (I) encompass functionalitiesincorporated into a compound of Formula (I), each functionalityappearing at any location within the disclosed compound may beindependently selected, and as appropriate, independently and/oroptionally substituted.

As used herein, the terms “independently selected,” or “each selected”refer to functional variables in a substituent list that may be attachedmore than once on the structure of a core molecule, where the pattern ofsubstitution at each occurrence is independent of the pattern at anyother occurrence. Further, the use of a generic substituent on a corestructure for a compound provided herein is understood to include thereplacement of the generic substituent with specie substituents that areincluded within the particular genus, e.g., aryl may be independentlyreplaced with phenyl or naphthalenyl (also referred to as naphthyl) andthe like, such that the resulting compound is intended to be includedwithin the scope of the compounds described herein.

As used herein, the term “each instance of” when used in a phrase suchas“ . . . aryl, aryl-C₁₋₈alkyl, heterocyclyl and heterocyclyl-C₁₋₈alkyl,wherein each instance of aryl and heterocyclyl is optionally substitutedwith one or two substituents . . . ” is intended to include optional,independent substitution on each of the aryl and heterocyclyl rings andon the aryl and heterocyclyl portions of aryl-C₁₋₈alkyl andheterocyclyl-C₁₋₈alkyl.

As used herein, the term “optionally substituted” means that thespecified substituent variables, groups, radicals or moieties representthe scope of the genus and may be independently chosen as needed toreplace one or more hydrogen atoms on the designated atom of attachmentof a core molecule.

As used herein, the terms “stable compound” or “stable structure” mean acompound that is sufficiently robust to be isolated to a useful degreeof purity from a reaction mixture and formulations thereof into anefficacious therapeutic agent.

Compound names provided herein were obtained using ACD Labs Index Namesoftware provided by ACD Labs and/or ChemDraw Ultra software provided byCambridgeSoft®. When the compound name disclosed herein conflicts withthe structure depicted, the structure shown will supercede the use ofthe name to define the compound intended. Nomenclature for substituentradicals defined herein may differ slightly from the chemical name fromwhich they are derived; one skilled in the art will recognize that thedefinition of the substituent radical is intended to include the radicalas found in the chemical name.

As used herein the term “aberrant” refers to a deviation from the normof, e.g., the average healthy subject or a cell(s) or tissue sample froma healthy subject. The term “aberrant expression,” as used herein,refers to abnormal expression (up-regulated or down-regulated resultingin an excessive or deficient amount thereof) of a gene product (e.g.,RNA transcript or protein) by a cell, tissue sample, or subject relativeto a corresponding normal, healthy cell, tissue sample or subject. In aspecific embodiment, the “aberrant expression” refers to an alteredlevel of a gene product (e.g., RNA transcript or protein) in a cell,tissue sample, or subject relative to a corresponding normal, healthycell, tissue sample or subject. The term “aberrant amount” as usedherein refers to an altered level of a gene product (e.g., RNA, protein,polypeptide, or peptide) in a cell, tissue sample, or subject relativeto a corresponding normal, healthy cell, tissue sample or subject. Inspecific embodiments, the amount of a gene product (e.g., RNA, protein,polypeptide, or peptide) in a cell, tissue sample, or subject relativeto a corresponding cell or tissue sample from a healthy subject or ahealthy subject, is considered aberrant if it is 1, 1.5, 2, 2.5, 3, 3.5,4, 4.5, 5, 5.5, 6-fold or more above or below the amount of the geneproduct in the corresponding cell or tissue sample from a healthysubject or healthy subject.

As used herein, the phrase “non-endogenous REMS” refers to a REMS notnaturally found to be part of an RNA sequence or naturally encoded by aDNA sequence. In other words, the hand of man is required to manipulatethe RNA or DNA sequence to introduce the REMS or the nucleotide sequenceencoding the REMS.

As used herein, the term “substantial change” in the context of theamount of one or more RNA transcripts (e.g., rRNA, tRNA, miRNA, siRNA,lncRNA, pre-mRNA or mRNA transcripts), an alternative splice variantthereof or an isoform thereof, or one or more proteins thereof, eachexpressed as the product of one or more of genes, means that the amountof such products changes by a statistically significant amount such as,in a nonlimiting example, a p value less than a value selected from 0.1,0.01, 0.001, or 0.0001.

As used herein, the terms “subject” and “patient” are usedinterchangeably to refer to an animal or any living organism havingsensation and the power of voluntary movement, and which requires forits existence oxygen and organic food. Non-limiting examples includemembers of the human, equine, porcine, bovine, rattus, murine, canineand feline species. In some embodiments, the subject is a mammal or awarm-blooded vertebrate animal. In certain embodiments, the subject is anon-human animal. In specific embodiments, the subject is a human.

As used herein, the term “functional protein” refers to a form of aprotein that retains a certain biological function or the functions of afull length protein or protein isoform encoding by a gene.

As used herein, in the context of a functional protein produced from anartificial construct, the term “produce substantially less” means thatthe amount of functional protein in the absence of a compound describedherein is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 70%,75%, 80%, 85%, 90%, 95%, 98%, or 100% less than the amount of functionalprotein produced in the presence of the compound.

Compound Forms

As used herein, the terms “a compound of Formula (Ia),” “a compound ofFormula (Ia1),” “a compound of Formula (Ia2),” “a compound of Formula(Ia3),” “a compound of Formula (Ia4),” “a compound of Formula (II),” “acompound of Formula (IIa),” “a compound of Formula (IIa1),” “a compoundof Formula (IIa2),” “a compound of Formula (IIa3),” “a compound ofFormula (IIa4),” “a compound of Formula (III),” “a compound of Formula(IIIa),” “a compound of Formula (IIIa1),” “a compound of Formula(IIIa2),” “a compound of Formula (IIIa3),” “a compound of Formula(IIIa4),” “a compound of Formula (IV),” “a compound of Formula (IVa),”“a compound of Formula (IVa1),” “a compound of Formula (IVa2),” “acompound of Formula (V),” “a compound of Formula (Va),” “a compound ofFormula (Val),” “a compound of Formula (Va2),” “a compound of Formula(VI),” “a compound of Formula (VIa),” “a compound of Formula (VIa1),” “acompound of Formula (VIa2),” “a compound of Formula (VIa3),” “a compoundof Formula (VIa4),” “a compound of Formula (VII),” “a compound ofFormula (VIIa),” “a compound of Formula (VIIa1),” “a compound of Formula(VIIa2),” “a compound of Formula (VIII),” “a compound of Formula(VIIIa),” “a compound of Formula (VIIIa1),” “a compound of Formula(VIIIa2),” “a compound of Formula (IX),” “a compound of Formula (IXa),”“a compound of Formula (IXa1),” “a compound of Formula (IXa2),” “acompound of Formula (IXa3),” “a compound of Formula (IXa4),” “a compoundof Formula (X),” “a compound of Formula (Xa),” “a compound of Formula(Xa1),” “a compound of Formula (Xa2),” “a compound of Formula (XI),” “acompound of Formula (XIa),” “a compound of Formula (XIa1),” “a compoundof Formula (XIa2),” “a compound of Formula (XII),” “a compound ofFormula (XIIa),” “a compound of Formula (XIIa1),” “a compound of Formula(XIIa2),” “a compound of Formula (XIIa3),” “a compound of Formula(XIIa4),” “a compound of Formula (XIII),” “a compound of Formula(XIIIa),” “a compound of Formula (XIIIa1),” “a compound of Formula(XIIIa2),” “a compound of Formula (XIV),” “a compound of Formula(XIVa),” “a compound of Formula (XIVa1),” and “a compound of Formula(XIVa2),” each refer to subgenera of the compound of Formula (I) or aform thereof.

Rather than repeat embodiments for the various subgenera of the compoundof Formula (I), in certain embodiments, the term “a compound of Formula(I) or a form thereof” is used to inclusively to refer to a compound ofFormula (Ia) or a form thereof, a compound of Formula (Ia1) or a formthereof, a compound of Formula (Ia2) or a form thereof, a compound ofFormula (Ia3) or a form thereof, a compound of Formula (Ia4) or a formthereof, a compound of Formula (II) or a form thereof, a compound ofFormula (IIa) or a form thereof, a compound of Formula (IIa1) or a formthereof, a compound of Formula (IIa2) or a form thereof, a compound ofFormula (IIa3) or a form thereof, a compound of Formula (IIa4) or a formthereof, a compound of Formula (III) or a form thereof, a compound ofFormula (IIIa) or a form thereof, a compound of Formula (IIIa1) or aform thereof, a compound of Formula (IIIa2) or a form thereof, acompound of Formula (IIIa3) or a form thereof, a compound of Formula(IIIa4) or a form thereof, a compound of Formula (IV) or a form thereof,a compound of Formula (IVa) or a form thereof, a compound of Formula(IVa1) or a form thereof, a compound of Formula (IVa2) or a formthereof, a compound of Formula (V) or a form thereof, a compound ofFormula (Va) or a form thereof, a compound of Formula (Va1) or a formthereof, a compound of Formula (Va2) or a form thereof, a compound ofFormula (VI) or a form thereof, a compound of Formula (VIa) or a formthereof, a compound of Formula (VIa1) or a form thereof, a compound ofFormula (VIa2) or a form thereof, a compound of Formula (VIa3) or a formthereof, a compound of Formula (VIa4) or a form thereof, a compound ofFormula (VII) or a form thereof, a compound of Formula (VIIa) or a formthereof, a compound of Formula (VIIa1) or a form thereof, a compound ofFormula (VIIa2) or a form thereof, a compound of Formula (VIII) or aform thereof, a compound of Formula (VIIIa) or a form thereof, acompound of Formula (VIIIa1) or a form thereof, a compound of Formula(VIIIa2) or a form thereof, a compound of Formula (IX) or a formthereof, a compound of Formula (IXa) or a form thereof, a compound ofFormula (IXa1) or a form thereof, a compound of Formula (IXa2) or a formthereof, a compound of Formula (IXa3) or a form thereof, a compound ofFormula (IXa4) or a form thereof, a compound of Formula (X) or a formthereof, a compound of Formula (Xa) or a form thereof, a compound ofFormula (Xa1) or a form thereof, a compound of Formula (Xa2) or a formthereof, a compound of Formula (XI) or a form thereof, a compound ofFormula (XIa) or a form thereof, a compound of Formula (XIa1) or a formthereof, a compound of Formula (XIa2) or a form thereof, a compound ofFormula (XII) or a form thereof, a compound of Formula (XIIa) or a formthereof, a compound of Formula (XIIa1) or a form thereof, a compound ofFormula (XIIa2) or a form thereof, a compound of Formula (XIIa3) or aform thereof, a compound of Formula (XIIa4) or a form thereof, acompound of Formula (XIII) or a form thereof, a compound of Formula(XIIIa) or a form thereof, a compound of Formula (XIIIa1) or a formthereof, a compound of Formula (XIIIa2) or a form thereof, a compound ofFormula (XIV) or a form thereof, a compound of Formula (XIVa) or a formthereof, a compound of Formula (XIVa1) or a form thereof or a compoundof Formula (XIVa2) or a form thereof, either separately or together.

Thus, embodiments and references to “a compound of Formula (I)” areintended to be inclusive of compounds of Formula (Ia), Formula (Ia1),Formula (Ia2), Formula (Ia3), Formula (Ia4), Formula (II), Formula(IIa), Formula (IIa1), Formula (IIa2), Formula (IIa3), Formula (IIa4),Formula (III), Formula (IIIa), Formula (IIIa1), Formula (IIIa2), Formula(IIIa3), Formula (IIIa4), Formula (IV), Formula (IVa), Formula (IVa1),Formula (IVa2), Formula (V), Formula (Va), Formula (Va1), Formula (Va2),Formula (VI), Formula (VIa), Formula (VIa1), Formula (VIa2), Formula(VIa3), Formula (VIa4), Formula (VII), Formula (VIIa), Formula (VIIa1),Formula (VIIa2), Formula (VIII), Formula (VIIIa), Formula (VIIIa1),Formula (VIIIa2), Formula (IX), Formula (IXa), Formula (IXa1), Formula(IXa2), Formula (IXa3), Formula (IXa4), Formula (X), Formula (Xa),Formula (Xa1), Formula (Xa2), Formula (XI), Formula (XIa), Formula(XIa1), Formula (XIa2), Formula (XII), Formula (XIIa), Formula (XIIa1),Formula (XIIa2), Formula (XIIa3), Formula (XIIa4), Formula (XIII),Formula (XIIIa), Formula (XIIIa1), Formula (XIIIa2), Formula (XIV),Formula (XIVa), Formula (XIVa1) and Formula (XIVa2).

As used herein, the term “form” means a compound of Formula (I) selectedfrom a free acid, free base, salt, isotopologue, stereoisomer, racemate,enantiomer, diastereomer, or tautomer thereof.

In certain embodiments described herein, the form of the compound ofFormula (I) is a selected from a salt, isotopologue, stereoisomer,racemate, enantiomer, diastereomer or tautomer thereof.

In certain embodiments described herein, the form of the compound ofFormula (I) is a selected from a free acid, isotopologue, stereoisomer,racemate, enantiomer, diastereomer or tautomer thereof.

In certain embodiments described herein, the form of the compound ofFormula (I) is a selected from a free base, isotopologue, stereoisomer,racemate, enantiomer, diastereomer or tautomer thereof.

In certain embodiments described herein, the form of the compound ofFormula (I) is a free acid, free base or salt thereof.

In certain embodiments described herein, the form of the compound ofFormula (I) is an isotopologue thereof.

In certain embodiments described herein, the form of the compound ofFormula (I) is a stereoisomer, racemate, enantiomer or diastereomerthereof.

In certain embodiments described herein, the form of the compound ofFormula (I) is a tautomer thereof.

In certain embodiments described herein, the form of the compound ofFormula (I) is a pharmaceutically acceptable form.

In certain embodiments described herein, the compound of Formula (I) ora form thereof is isolated for use.

As used herein, the term “isolated” means the physical state of acompound of Formula (I) or a form thereof after being isolated and/orpurified from a synthetic process (e.g., from a reaction mixture) ornatural source or combination thereof according to an isolation orpurification process or processes described herein or which are wellknown to the skilled artisan (e.g., chromatography, recrystallizationand the like) in sufficient purity to be characterizable by standardanalytical techniques described herein or well known to the skilledartisan.

As used herein, the term “protected” means that a functional group on acompound of Formula (I) is in a form modified to preclude undesired sidereactions at the protected site when the compound is subjected to areaction. Suitable protecting groups will be recognized by those withordinary skill in the art as well as by reference to standard textbookssuch as, for example, T. W. Greene et al, Protective Groups in OrganicSynthesis (1991), Wiley, New York.

Prodrugs of a compound of Formula (I) or a form thereof are alsocontemplated herein.

As used herein, the term “prodrug” means that a functional group on acompound of Formula (I) is in a form (e.g., acting as an active orinactive drug precursor) that is transformed in vivo to yield an activeor more active compound of Formula (I) or a form thereof. Thetransformation may occur by various mechanisms (e.g., by metabolicand/or non-metabolic chemical processes), such as, for example, byhydrolysis and/or metabolism in blood, liver and/or other organs andtissues. A discussion of the use of prodrugs is provided by V. J.Stella, et. al., “Biotechnology: Pharmaceutical Aspects, Prodrugs:Challenges and Rewards,” American Association of PharmaceuticalScientists and Springer Press, 2007.

In one example, when a compound of Formula (I) or a form thereofcontains a carboxylic acid functional group, a prodrug can comprise anester formed by the replacement of the hydrogen atom of the acid groupwith a functional group such as alkyl and the like. In another example,when a compound of Formula (I) or a form thereof contains an alcoholfunctional group, a prodrug can be formed by the replacement of thehydrogen atom of the alcohol group with a functional group such as alkylor substituted carbonyl and the like. In another example, when acompound of Formula (I) or a form thereof contains an amine functionalgroup, a prodrug can be formed by the replacement of one or more aminehydrogen atoms with a functional group such as alkyl or substitutedcarbonyl. In another example, when a compound of Formula (I) or a formthereof contains a hydrogen substituent, a prodrug can be formed by thereplacement of one or more hydrogen atoms with an alkyl substituent.

Pharmaceutically acceptable prodrugs of compounds of Formula (I) or aform thereof include those compounds substituted with one or more of thefollowing groups: carboxylic acid esters, sulfonate esters, amino acidesters phosphonate esters, mono-, di- or triphosphate esters or alkylsubstituents where appropriate. As described herein, it is understood bya person of ordinary skill in the art that one or more of suchsubstituents may be used to provide a compound of Formula (I) or a formthereof for use as a prodrug.

The compounds of Formula (I) can form salts which are intended to beincluded within the scope of this description. Reference to a compoundof Formula (I) herein is understood to include reference to saltsthereof, unless otherwise indicated. The term “salt(s)”, as employedherein, denotes acidic salts formed with inorganic and/or organic acids,as well as basic salts formed with inorganic and/or organic bases. Inaddition, when a compound of Formula (I) contains both a basic moiety,such as, but not limited to a pyridine or imidazole, and an acidicmoiety, such as, but not limited to a carboxylic acid, zwitterions(“inner salts”) may be formed and are included within the term “salt(s)”as used herein.

The term “pharmaceutically acceptable salt(s)”, as used herein, meansthose salts of compounds described herein that are safe and effective(i.e., non-toxic, physiologically acceptable) for use in mammals andthat possess biological activity, although other salts are also useful.Salts of the compounds of Formula (I) may be formed, for example, byreacting a compound of Formula (I) with an amount of acid or base, suchas an equivalent or stoichiometric amount, in a medium such as one inwhich the salt precipitates or in an aqueous medium followed bylyophilization.

Pharmaceutically acceptable salts include one or more salts of acidic orbasic groups present in compounds described herein. Embodiments of acidaddition salts include, and are not limited to, acetate, acid phosphate,ascorbate, benzoate, benzenesulfonate, bisulfate, bitartrate, borate,butyrate, chloride, citrate, camphorate, camphorsulfonate,ethanesulfonate, formate, fumarate, gentisinate, gluconate, glucaronate,glutamate, hydrobromide, hydrochloride, dihydrochloride, hydroiodide,isonicotinate, lactate, maleate, methanesulfonate, naphthalenesulfonate,nitrate, oxalate, pamoate, pantothenate, phosphate, propionate,saccharate, salicylate, succinate, sulfate, tartrate, thiocyanate,toluenesulfonate (also known as tosylate), trifluoroacetate salts andthe like. One or more embodiments of acid addition salts include achloride, hydrochloride, dihydrochloride, trihydrochloride,hydrobromide, acetate, diacetate or trifluoroacetate salt. Moreparticular embodiments include a chloride, hydrochloride,dihydrochloride, hydrobromide or trifluoroacetate salt.

Additionally, acids which are generally considered suitable for theformation of pharmaceutically useful salts from basic pharmaceuticalcompounds are discussed, for example, by P. Stahl et al, Camille G.(eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use.(2002) Zurich: Wiley-VCH; S. Berge et al, Journal of PharmaceuticalSciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics(1986) 33, 201-217; Anderson et al, The Practice of Medicinal Chemistry(1996), Academic Press, New York; and in The Orange Book (see, websitefor Food & Drug Administration, Washington, D.C.). These disclosures areincorporated herein by reference thereto.

Suitable basic salts include, but are not limited to, aluminum,ammonium, calcium, lithium, magnesium, potassium, sodium, zinc, anddiethanolamine salts. Certain compounds described herein can also formpharmaceutically acceptable salts with organic bases (for example,organic amines) such as, but not limited to, dicyclohexylamines,tert-butyl amines and the like, and with various amino acids such as,but not limited to, arginine, lysine and the like. Basicnitrogen-containing groups may be quarternized with agents such as loweralkyl halides (e.g., methyl, ethyl, and butyl chlorides, bromides andiodides), dialkyl sulfates (e.g., dimethyl, diethyl, and dibutylsulfates), long chain halides (e.g., decyl, lauryl, and stearylchlorides, bromides and iodides), aralkyl halides (e.g., benzyl andphenethyl bromides), and others.

All such acid salts and base salts are intended to be pharmaceuticallyacceptable salts within the scope of the description herein and all suchacid and base salts are considered equivalent to the free forms of thecorresponding compounds for the purposes described herein.

Compounds of Formula I and forms thereof may further exist in atautomeric form. All such tautomeric forms are contemplated herein aspart of the present description.

The compounds of Formula (I) may contain asymmetric or chiral centers,and, therefore, may exist in different stereoisomeric forms. The presentdescription is intended to include all stereoisomeric forms of thecompounds of Formula (I) as well as mixtures thereof, including racemicmixtures.

The compounds of Formula (I) described herein may include one or morechiral centers, and as such may exist as racemic mixtures (R/S) or assubstantially pure enantiomers and diastereomers. The compounds may alsoexist as substantially pure (R) or (S) enantiomers (when one chiralcenter is present). In one embodiment, the compounds of Formula (I)described herein are (S) isomers and may exist as enantiomerically purecompositions substantially comprising only the (S) isomer. In anotherembodiment, the compounds of Formula (I) described herein are (R)isomers and may exist as enantiomerically pure compositionssubstantially comprising only the (R) isomer. As one of skill in the artwill recognize, when more than one chiral center is present, thecompounds of Formula (I) described herein may also include portionsdescribed as an (R,R), (R,S), (S,R) or (S,S) isomer, as defined by IUPACNomenclature Recommendations.

As used herein, the term “substantially pure” refers to compoundsconsisting substantially of a single isomer in an amount greater than orequal to 90%, in an amount greater than or equal to 92%, in an amountgreater than or equal to 95%, in an amount greater than or equal to 98%,in an amount greater than or equal to 99%, or in an amount equal to 100%of the single isomer.

In one aspect, a compound of Formula (I) is a substantially pure (S)enantiomer present in an amount greater than or equal to 90%, in anamount greater than or equal to 92%, in an amount greater than or equalto 95%, in an amount greater than or equal to 98%, in an amount greaterthan or equal to 99%, or in an amount equal to 100%.

In one aspect, a compound of Formula (I) is a substantially pure (R)enantiomer present in an amount greater than or equal to 90%, in anamount greater than or equal to 92%, in an amount greater than or equalto 95%, in an amount greater than or equal to 98%, in an amount greaterthan or equal to 99%, or in an amount equal to 100%.

As used herein, a “racemate” is any mixture of isometric forms that arenot “enantiomerically pure”, including mixtures such as, withoutlimitation, in a ratio of about 50/50, about 60/40, about 70/30, about80/20, about 85/15 or about 90/10.

In addition, the present description embraces all geometric andpositional isomers. For example, if a compound of Formula (I)incorporates a double bond or a fused ring, both the cis- andtrans-forms, as well as mixtures, are embraced within the scope of thedescription herein.

Diastereomeric mixtures can be separated into their individualdiastereomers on the basis of their physical chemical differences bymethods well known to those skilled in the art, such as, for example, bychromatography and/or fractional crystallization. Enantiomers can beseparated by use of chiral HPLC column or other chromatographic methodsknown to those skilled in the art.

Enantiomers can also be separated by converting the enantiomeric mixtureinto a diastereomeric mixture by reaction with an appropriate opticallyactive compound (e.g., chiral auxiliary such as a chiral alcohol orMosher's acid chloride), separating the diastereomers and converting(e.g., hydrolyzing) the individual diastereomers to the correspondingpure enantiomers. Also, some of the compounds of Formula (I) may beatropisomers (e.g., substituted biaryls) and are considered part of thisdescription.

All stereoisomer forms (for example, geometric isomers, optical isomers,positional isomers and the like) of the present compounds (includingsalts, solvates, esters and prodrugs and transformed prodrugs thereof)which may exist due to asymmetric carbons on various substituents,including enantiomeric forms (which may exist even in the absence ofasymmetric carbons), rotameric forms, atropisomers, diastereomeric formsand regioisomeric forms are contemplated within the scope of thedescription herein. For example, if a compound of Formula (I)incorporates a double bond or a fused ring, both the cis- andtrans-forms, as well as mixtures thereof, are embraced within the scopeof the description herein. Also, for example, all keto-enol andimine-enamine tautomeric forms of the compounds are included in thedescription herein. Individual stereoisomers of the compounds of Formula(I) described herein may, for example, be substantially free of otherisomers, or may be present in a racemic mixture, as described supra.

The use of the terms “salt,” “prodrug” and “transformed prodrug” areintended to equally apply to the salts, prodrugs and transformedprodrugs of all contemplated isotopologues, stereoisomers, racemates ortautomers of the instant compounds.

The term “isotopologue” refers to isotopically-enriched compounds whichare identical to those recited herein, but for the fact that one or moreatoms are replaced by an atom having an atomic mass or mass numberdifferent from the atomic mass or mass number usually found in nature.Examples of isotopes that can be incorporated into compounds describedherein include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorus, fluorine and chlorine, such as H², H³, C¹³, C¹⁴, N¹⁵, O¹⁸,O¹⁷, P³¹, P³², S³⁵, F¹⁸, Cl³⁵ and Cl³⁶, respectively, each of which isalso within the scope of this description.

Certain isotopically-enriched compounds described herein (e.g., thoselabeled with H³ and C¹⁴) are useful in compound and/or substrate tissuedistribution assays. Tritiated (i.e., H³) and carbon-14 (i.e., C¹⁴)isotopes are particularly preferred for their ease of preparation anddetectability. Further, substitution with heavier isotopes such asdeuterium (i.e., “deuterium enriched”) may afford certain therapeuticadvantages resulting from greater metabolic stability (e.g., increasedin vivo half-life or reduced dosage requirements) and hence may bepreferred in some circumstances. Isotopically-enriched compounds ofFormula (I) can generally be prepared using procedures known to personsof ordinary skill in the art by substituting an appropriateisotopically-enriched reagent for a non-isotopically-enriched reagent.

When the compounds are enriched with deuterium, thedeuterium-to-hydrogen ratio on the deuterated atoms of the moleculesubstantially exceeds the naturally occurring deuterium-to-hydrogenratio.

An embodiment described herein may include an isotopologue form of thecompound of Formula (I), wherein the isotopologue is substituted on oneor more atom members of the compound of Formula (I) with one or moredeuterium atoms in place of one or more hydrogen atoms.

An embodiment described herein may include a compound of Formula (I) andforms thereof, wherein a carbon atom may have from 1 to 3 hydrogen atomsoptionally replaced with deuterium.

One or more compounds described herein may exist in unsolvated as wellas solvated forms with pharmaceutically acceptable solvents such aswater, ethanol, and the like, and the description herein is intended toembrace both solvated and unsolvated forms.

As used herein, the term “solvate” means a physical association of acompound described herein with one or more solvent molecules. Thisphysical association involves varying degrees of ionic and covalentbonding, including hydrogen bonding. In certain instances the solvatewill be capable of isolation, for example when one or more solventmolecules are incorporated in the crystal lattice of the crystallinesolid. As used herein, “solvate” encompasses both solution-phase andisolatable solvates. Non-limiting examples of suitable solvates includeethanolates, methanolates, and the like.

One or more compounds described herein may optionally be converted to asolvate. Preparation of solvates is generally known. A typical,non-limiting process involves dissolving a compound in a desired amountof the desired solvent (organic or water or mixtures thereof) at ahigher than ambient temperature, and cooling the solution at a ratesufficient to form crystals which are then isolated by standard methods.Analytical techniques such as, for example infrared spectroscopy, showthe presence of the solvent (or water) in the crystals as a solvate (orhydrate).

As used herein, the term “hydrate” means a solvate wherein the solventmolecule is water.

Polymorphic crystalline and amorphous forms of the compounds of Formula(I), and of the salts, solvates, esters and prodrugs of the compounds ofFormula (I), are further intended to be included in the scope of thecompounds described herein

Methods for Determining which Genes May be Modulated by the Compounds

In another aspect, provided herein are methods for determining whetherthe splicing of the precursor RNA of a gene is likely to be modulated bya compound of Formula (I) or a form thereof, comprising searching forthe presence of a REMS in the gene sequence, wherein the presence of aREMS upstream of a 3′ splice site and a branch point in the genesequence indicates that the splicing of the precursor RNA of the gene islikely to be modulated by the compound of Formula (I) or a form thereof,and the absence of a REMS upstream of a 3′ splice site and a branchpoint in the gene sequence indicates that the splicing of the precursorRNA of the gene is unlikely to be modulated by the compound of Formula(I) or a form thereof. In certain embodiments, a compound of Formula (I)is a compound of Formula (II), Formula (III), Formula (IV), Formula (V),Formula (VI), Formula (VII), Formula (VIII), Formula (IX), Formula (X),Formula (XI), Formula (XII), Formula (XIII), or Formula (XIV) describedherein. In specific embodiments, the methods further comprise searchingfor the presence of a 3′ splice site and/or a branch point in the genesequence downstream of the REMS.

In another aspect, provided herein are methods for determining whetherthe amount of a product (e.g., an mRNA transcript or protein) of a geneis likely to be modulated by a compound of Formula (I) or a formthereof, comprising searching for the presence of a REMS in the genesequence, wherein the presence of a REMS upstream of a 3′ splice siteand a branch point in the gene sequence indicates that the amount of aproduct (e.g., an mRNA transcript or protein) of the gene is likely tobe modulated by the compound of Formula (I) or a form thereof, and theabsence of a REMS upstream of a 3′ splice site and a branch point in thegene sequence indicates that the amount of a product (e.g., an mRNAtranscript or protein) of the gene is unlikely to be modulated by thecompound of Formula (I) or a form thereof. In certain embodiments, acompound of Formula (I) is a compound of Formula (II), Formula (III),Formula (IV), Formula (V), Formula (VI), Formula (VII), Formula (VIII),Formula (IX), Formula (X), Formula (XI), Formula (XII), Formula (XIII),or Formula (XIV) described herein. In specific embodiments, the methodsfurther comprise searching for the presence of a 3′ splice site and/or abranch point in the gene sequence downstream of the REMS.

The step of searching for the presence of a REMS, a 3′ splice site,and/or a branch point in the gene sequence described herein can beperformed by a computer system comprising a memory storing instructionsfor searching the presence of the REMS, the 3′ splice site, and/or thebranch point in the gene sequence, or can be performed manually.

In certain embodiments, the splicing of a precursor RNA containing aREMS is assessed by contacting a compound described herein with theprecursor RNA in cell cultured in tissue culture. In some embodiments,the splicing of a precursor RNA containing a REMS is assessed bycontacting a compound described herein with the precursor RNA in acell-free extract. In a specific embodiment, the compound is one knownto modulate the splicing of a precursor RNA containing a REMS. See,e.g., the section below relating to methods for determining whether acompound modulates the expression of certain genes, and the examplebelow for techniques that could be used in these assessments.

Methods for Determining which Compounds of Formula (I) Modulate theExpression of Certain Genes

Provided herein are methods for determining whether a compound ofFormula (I) or a form thereof modulates the amount of one, two, three ormore RNA transcripts (e.g., pre-mRNA or mRNA transcripts or isoformsthereof) of one, two, three or more genes. In some embodiments, the geneis any one of the genes disclosed in Tables 1-4 or any one of the genesdisclosed in Table 6. In certain embodiments, the gene is not a genedisclosed in Tables 1-4. In some embodiments, the gene is not a genedisclosed in Table 6. In other embodiments, the gene is a gene disclosedin Table 6. In a specific embodiment, the gene is ERGIC3.

In one embodiment, provided herein is a method for determining whether acompound of Formula (I) or a form thereof modulates the amount of an RNAtranscript, comprising: (a) contacting a cell(s) with a compound ofFormula (I) or a form thereof, and (b) determining the amount of the RNAtranscript produced by the cell(s), wherein an alteration in the amountof the RNA transcript in the presence of the compound relative to theamount of the RNA transcript in the absence of the compound or thepresence of a negative control (e.g., a vehicle control such as PBS orDMSO) indicates that the compound of Formula (I) or a form thereofmodulates the amount of the RNA transcript. In another embodiment,provided herein is a method for determining whether a compound ofFormula (I) or a form thereof modulates the amount of an RNA transcript(e.g., an mRNA transcript), comprising: (a) contacting a first cell(s)with a compound of Formula (I) or a form thereof, (b) contacting asecond cell(s) with a negative control (e.g., a vehicle control, such asPBS or DMSO); and (c) determining the amount of the RNA transcriptproduced by the first cell(s) and the second cell(s); and (d) comparingthe amount of the RNA transcript produced by the first cell(s) to theamount of the RNA transcript expressed by the second cell(s), wherein analteration in the amount of the RNA transcript produced by the firstcell(s) relative to the amount of the RNA transcript produced by thesecond cell(s) indicates that the compound of Formula (I) or a formthereof modulates the amount of the RNA transcript. In certainembodiments, the contacting of the cell(s) with the compound occurs incell culture. In other embodiments, the contacting of the cell(s) withthe compound occurs in a subject, such as a non-human animal subject.

In another embodiment, provided herein is a method for determiningwhether a compound of Formula (I) or a form thereof modulates thesplicing of an RNA transcript (e.g., an mRNA transcript), comprising:(a) culturing a cell(s) in the presence of a compound of Formula (I) ora form thereof; and (b) determining the amount of the two or more RNAtranscript splice variants produced by the cell(s), wherein analteration in the amount of the two or more RNA transcript in thepresence of the compound relative to the amount of the two or more RNAtranscript splice variants in the absence of the compound or thepresence of a negative control (e.g., a vehicle control such as PBS orDMSO) indicates that the compound of Formula (I) or a form thereofmodulates the splicing of the RNA transcript.

In another embodiment, provided herein is a method for determiningwhether a compound of Formula (I) or a form thereof modulates thesplicing of an RNA transcript (e.g., an mRNA transcript), comprising:(a) culturing a cell(s) in the presence of a compound of Formula (I) ora form thereof; (b) isolating two or more RNA transcript splice variantsfrom the cell(s) after a certain period of time; and (c) determining theamount of the two or more RNA transcript splice variants produced by thecell(s), wherein an alteration in the amount of the two or more RNAtranscript in the presence of the compound relative to the amount of thetwo or more RNA transcript splice variants in the absence of thecompound or the presence of a negative control (e.g., a vehicle controlsuch as PBS or DMSO) indicates that the compound of Formula (I) or aform thereof modulates the splicing of the RNA transcript. In anotherembodiment, provided herein is a method for determining whether acompound of Formula (I) or a form thereof modulates the splicing of anRNA transcript (e.g., an mRNA transcript), comprising (a) culturing afirst cell(s) in the presence of a compound of Formula (I) or a formthereof, (b) culturing a second cell(s) in the presence of a negativecontrol (e.g., a vehicle control, such as PBS or DMSO); (c) isolatingtwo or more RNA transcript splice variants produced by the first cell(s)and isolating two or more RNA transcript splice variants produced by thesecond cell(s); (d) determining the amount of the two or more RNAtranscript splice variants produced by the first cell(s) and the secondcell(s); and (e) comparing the amount of the two or more RNA transcriptsplice variants produced by the first cell(s) to the amount of the twoor more RNA transcript splice variants produced by the second cell(s),wherein an alteration in the amount of the two or more RNA transcriptsplice variants produced by the first cell(s) relative to the amount ofthe two or more RNA transcript splice variants produced by the secondcell(s) indicates that the compound of Formula (I) or a form thereofmodulates the splicing of the RNA transcript.

In another embodiment, provided herein is a method for determiningwhether a compound of Formula (I) or a form thereof modulates the amountof an RNA transcript (e.g., an mRNA transcript), comprising: (a)contacting a cell-free system with a compound of Formula (I) or a formthereof, and (b) determining the amount of the RNA transcript producedby the cell-free system, wherein an alteration in the amount of the RNAtranscript in the presence of the compound relative to the amount of theRNA transcript in the absence of the compound or the presence of anegative control (e.g., a vehicle control such as PBS or DMSO) indicatesthat the compound of Formula (I) or a form thereof modulates the amountof the RNA transcript. In another embodiment, provided herein is amethod for determining whether a compound of Formula (I) or a formthereof modulates the amount of an RNA transcript (e.g., an mRNAtranscript), comprising: (a) contacting a first cell-free system with acompound of Formula (I) or a form thereof, (b) contacting a secondcell-free system with a negative control (e.g., a vehicle control, suchas PBS or DMSO); and (c) determining the amount of the RNA transcriptproduced by the first cell-free system and the second cell-free system;and (d) comparing the amount of the RNA transcript produced by the firstcell-free system to the amount of the RNA transcript expressed by thesecond cell-free system, wherein an alteration in the amount of the RNAtranscript produced by the first cell-free system relative to the amountof the RNA transcript produced by the second cell-free system indicatesthat the compound of Formula (I) or a form thereof modulates the amountof the RNA transcript. In certain embodiments, the cell-free systemcomprises purely synthetic RNA, synthetic or recombinant (purified)enzymes, and protein factors. In other embodiments, the cell-free systemcomprises RNA transcribed from a synthetic DNA template, synthetic orrecombinant (purified) enzymes, and protein factors. In otherembodiments, the cell-free system comprises purely synthetic RNA andnuclear extract. In other embodiments, the cell-free system comprisesRNA transcribed from a synthetic DNA template and nuclear extract. Inother embodiments, the cell-free system comprises purely synthetic RNAand whole cell extract. In other embodiments, the cell-free systemcomprises RNA transcribed from a synthetic DNA template and whole cellextract. In certain embodiments, the cell-free system additionallycomprises regulatory RNAs (e.g., microRNAs).

In another embodiment, provided herein is a method for determiningwhether a compound of Formula (I) or a form thereof modulates thesplicing of an RNA transcript (e.g., an mRNA transcript), comprising:(a) contacting a cell-free system with a compound of Formula (I) or aform thereof, and (b) determining the amount of two or more RNAtranscript splice variants produced by the cell-free system, wherein analteration in the amount of the two or more RNA transcript splicevariants in the presence of the compound relative to the amount of thetwo or more RNA transcript splice variants in the absence of thecompound or the presence of a negative control (e.g., a vehicle controlsuch as PBS or DMSO) indicates that the compound of Formula (I) or aform thereof modulates the splicing of the RNA transcript. In anotherembodiment, provided herein is a method for determining whether acompound of Formula (I) or a form thereof modulates the splicing of anRNA transcript (e.g., an mRNA transcript), comprising: (a) contacting afirst cell-free system with a compound of Formula (I) or a form thereof,(b) contacting a second cell-free system with a negative control (e.g.,a vehicle control, such as PBS or DMSO); and (c) determining the amountof two or more RNA transcript splice variants produced by the firstcell-free system and the second cell-free system; and (d) comparing theamount of the two or more RNA transcript splice variants produced by thefirst cell-free system to the amount of the RNA transcript expressed bythe second cell-free system, wherein an alteration in the amount of thetwo or more RNA transcript splice variants produced by the firstcell-free system relative to the amount of the two or more RNAtranscript splice variants produced by the second cell-free systemindicates that the compound of Formula (I) or a form thereof modulatesthe splicing of the RNA transcript. In certain embodiments, thecell-free system comprises purely synthetic RNA, synthetic orrecombinant (purified) enzymes, and protein factors. In otherembodiments, the cell-free system comprises RNA transcribed from asynthetic DNA template, synthetic or recombinant (purified) enzymes, andprotein factors. In other embodiments, the cell-free system comprisespurely synthetic RNA and nuclear extract. In other embodiments, thecell-free system comprises RNA transcribed from a synthetic DNA templateand nuclear extract. In other embodiments, the cell-free systemcomprises purely synthetic RNA and whole cell extract. In otherembodiments, the cell-free system comprises RNA transcribed from asynthetic DNA template and whole cell extract. In certain embodiments,the cell-free system additionally comprises regulatory RNAs (e.g.,microRNAs).

In another embodiment, provided herein is a method for determiningwhether a compound of Formula (I) or a form thereof modulates the amountof an RNA transcript (e.g., an mRNA transcript), comprising: (a)culturing a cell(s) in the presence of a compound of Formula (I) or aform thereof, (b) isolating the RNA transcript from the cell(s) after acertain period of time; and (c) determining the amount of the RNAtranscript produced by the cell(s), wherein an alteration in the amountof the RNA transcript in the presence of the compound relative to theamount of the RNA transcript in the absence of the compound or thepresence of a negative control (e.g., a vehicle control such as PBS orDMSO) indicates that the compound of Formula (I) or a form thereofmodulates the amount of the RNA transcript. In another embodiment,provided herein is a method for determining whether a compound ofFormula (I) or a form thereof modulates the amount of an RNA transcript(e.g., an mRNA transcript), comprising (a) culturing a first cell(s) inthe presence of a compound of Formula (I) or a form thereof, (b)culturing a second cell(s) in the presence of a negative control (e.g.,a vehicle control, such as PBS or DMSO); (c) isolating the RNAtranscript produced by the first cell(s) and isolating the RNAtranscript produced by the second cell(s); (d) determining the amount ofthe RNA transcript produced by the first cell(s) and the second cell(s);and (e) comparing the amount of the RNA transcript produced by the firstcell(s) to the amount of the RNA transcript produced by the secondcell(s), wherein an alteration in the amount of the RNA transcriptproduced by the first cell(s) relative to the amount of the RNAtranscript produced by the second cell(s) indicates that the compound ofFormula (I) or a form thereof modulates the amount of the RNAtranscript.

In certain embodiments, the cell(s) contacted or cultured with acompound of Formula (I) or a form thereof is a primary cell(s) from asubject. In some embodiments, the cell(s) contacted or cultured with acompound of Formula (I) or a form thereof is a primary cell(s) from asubject with a disease. In specific embodiments, the cell(s) contactedor cultured with a compound of Formula (I) or a form thereof is aprimary cell(s) from a subject with a disease associated with anaberrant amount of an RNA transcript(s) for a particular gene(s). Insome specific embodiments, the cell(s) contacted or cultured with acompound of Formula (I) or a form thereof is a primary cell(s) from asubject with a disease associated with an aberrant amount of anisoform(s) of a particular gene(s). In some embodiments, the cell(s)contacted or cultured with a compound of Formula (I) or a form thereofis a fibroblast (e.g., GM03813 or PNN 1-46 fibroblasts), an immune cell(e.g., a T cell, B cell, natural killer cell, macrophage), or a musclecell. In certain embodiments, the cell(s) contacted or cultured with acompound of Formula (I) or a form thereof is a cancer cell.

In certain embodiments, the cell(s) contacted or cultured with acompound of Formula (I) or a form thereof is from a cell line. In someembodiments, the cell(s) contacted or cultured with a compound ofFormula (I) or a form thereof is a cell line derived from a subject witha disease. In certain embodiments, the cell(s) contacted or culturedwith a compound of Formula (I) or a form thereof is from a cell lineknown to have aberrant RNA transcript levels for a particular gene(s).In specific embodiments, the cell(s) contacted or cultured with acompound of Formula (I) or a form thereof is from a cell line derivedfrom a subject with a disease known to have aberrant RNA transcriptlevels for a particular gene(s). In certain embodiments, the cell(s)contacted or cultured with a compound of Formula (I) or a form thereofis a cancer cell line. In some specific embodiments, the cell(s)contacted or cultured with the compound of Formula (I) or a form thereofis from a cell line derived from a subject with a disease known to havean aberrant amount of an RNA isoform(s) and/or protein isoform(s) of aparticular gene(s). Non-limiting examples of cell lines include 293,3T3, 4T1, 721, 9L, A2780, A172, A20, A253, A431, A-549, ALC, B16, B35,BCP-1, BEAS-2B, bEnd.3, BHK, BR 293, BT2O, BT483, BxPC3, C2C12,C3H-10T1/2, C6/36, C6, Cal-27, CHO, COR-L23, COS, COV-434, CML T1, CMT,CRL7O3O, CT26, D17, DH82, DU145, DuCaP, EL4, EM2, EM3, EMT6, FM3, H1299,H69, HB54, HB55, HCA2, HEK-293, HeLa, Hepa1c1c7, HL-60, HMEC, Hs578T,HsS78Bst, HT-29, HTB2, HUVEC, Jurkat, J558L, JY, K562, Ku812, KCL22,KG1, KYO1, LNCap, Ma-Mel, MC-38, MCF-7, MCF-10A, MDA-MB-231, MDA-MB-468,MDA-MB-435, MDCK, MG63, MOR/0.2R, MONO-MAC 6, MRC5, MTD-1A, NCI-H69,NIH-3T3, NALM-1, NS0, NW-145, OPCN, OPCT, PNT-1A, PNT-2, Raji, RBL,RenCa, RIN-5F, RMA, Saos-2, Sf21, Sf9, SiHa, SKBR3, SKOV-3, T2, T-47D,T84, THP1, U373, U87, U937, VCaP, Vero, VERY, W138, WM39, WT-49, X63,YAC-1, and YAR cells. In one embodiment, the cells are from a patient.

In another embodiment, provided herein is a method for determiningwhether a compound of Formula (I) or a form thereof modulates the amountof an RNA transcript (e.g., an mRNA transcript), comprising: (a)contacting a tissue sample with a compound of Formula (I) or a formthereof, and (b) determining the amount of the RNA transcript producedby the tissue sample, wherein an alteration in the amount of the RNAtranscript in the presence of the compound relative to the amount of theRNA transcript in the absence of the compound or the presence of anegative control (e.g., a vehicle control such as PBS or DMSO) indicatesthat the compound of Formula (I) or a form thereof modulates the amountof the RNA transcript. In another embodiment, provided herein is amethod for determining whether a compound of Formula (I) or a formthereof modulates the amount of an RNA transcript (e.g., an mRNAtranscript), comprising: (a) contacting a first tissue sample with acompound of Formula (I) or a form thereof, (b) contacting a secondtissue sample with a negative control (e.g., a vehicle control, such asPBS or DMSO); and (c) determining the amount of the RNA transcriptproduced by the first tissue sample and the second tissue sample; and(d) comparing the amount of the RNA transcript produced by the firsttissue sample to the amount of the RNA transcript produced by the secondtissue sample, wherein an alteration in the amount of the RNA transcriptproduced by the first tissue sample relative to the amount of the RNAtranscript produced by the second tissue sample indicates that thecompound of Formula (I) or a form thereof modulates the amount of theRNA transcript. Any tissue sample containing cells may be used in theaccordance with these methods. In certain embodiments, the tissue sampleis a blood sample, a skin sample, a muscle sample, or a tumor sample.Techniques known to one skilled in the art may be used to obtain atissue sample from a subject.

In some embodiments, a dose-response assay is performed. In oneembodiment, the dose response assay comprises: (a) contacting a cell(s)with a concentration of a compound of Formula (I) or a form thereof, (b)determining the amount of the RNA transcript produced by the cell(s),wherein an alteration in the amount of the RNA transcript in thepresence of the compound relative to the amount of the RNA transcript inthe absence of the compound or the presence of a negative control (e.g.,a vehicle control such as PBS or DMSO) indicates that the compound ofFormula (I) or a form thereof modulates the amount of the RNAtranscript; (c) repeating steps (a) and (b), wherein the onlyexperimental variable changed is the concentration of the compound or aform thereof, and (d) comparing the amount of the RNA transcriptproduced at the different concentrations of the compound or a formthereof. In another embodiment, the dose response assay comprises: (a)culturing a cell(s) in the presence of a compound of Formula (I) or aform thereof, (b) isolating the RNA transcript from the cell(s) after acertain period of time; (c) determining the amount of the RNA transcriptproduced by the cell(s), wherein an alteration in the amount of the RNAtranscript in the presence of the compound relative to the amount of theRNA transcript in the absence of the compound or the presence of anegative control (e.g., a vehicle control such as PBS or DMSO) indicatesthat the compound of Formula (I) or a form thereof modulates the amountof the RNA transcript; (d) repeating steps (a), (b), and (c), whereinthe only experimental variable changed is the concentration of thecompound or a form thereof, and (e) comparing the amount of the RNAtranscript produced at the different concentrations of the compound or aform thereof. In another embodiments, the dose-response assay comprises:(a) contacting each well of a microtiter plate containing cells with adifferent concentration of a compound of Formula (I) or a form thereof,(b) determining the amount of an RNA transcript produced by cells ineach well; and (c) assessing the change of the amount of the RNAtranscript at the different concentrations of the compound or formthereof.

In one embodiment, the dose response assay comprises: (a) contacting acell(s) with a concentration of a compound of Formula (I) or a formthereof, wherein the cells are within the wells of a tissue culturecontainer (e.g., a 96-well plate) at about the same density within eachwell, and wherein the cells are contacted with different concentrationsof compound in different wells; (b) isolating the RNA from said cells ineach well; (c) determining the amount of the RNA transcript produced bythe cell(s) in each well; and (d) assessing change in the amount of theRNA transcript in the presence of one or more concentrations of compoundrelative to the amount of the RNA transcript in the presence of adifferent concentration of the compound or the absence of the compoundor the presence of a negative control (e.g., a vehicle control such asPBS or DMSO).

In certain embodiments, the contacting of the cell(s) with the compoundoccurs in cell culture. In other embodiments, the contacting of thecell(s) with the compound occurs in a subject, such as a non-humananimal subject.

In certain embodiments described herein, the cell(s) is contacted orcultured with a compound of Formula (I) or a form thereof, or a tissuesample is contacted with a compound of Formula (I) or a form thereof, ora negative control for a period of 15 minutes, 30 minutes, 45 minutes, 1hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 8 hours, 12 hours, 18hours, 24 hours, 48 hours, 72 hours or more. In other embodimentsdescribed herein, the cell(s) is contacted or cultured with a compoundof Formula (I) or a form thereof, or a tissue sample is contacted with acompound of Formula (I) or a form thereof, or a negative control for aperiod of 15 minutes to 1 hour, 1 to 2 hours, 2 to 4 hours, 6 to 12hours, 12 to 18 hours, 12 to 24 hours, 28 to 24 hours, 24 to 48 hours,48 to 72 hours.

In certain embodiments described herein, the cell(s) is contacted orcultured with a certain concentration of a compound of Formula (I) or aform thereof, or a tissue sample is contacted with a certainconcentration of a compound of Formula (I) or a form thereof, whereinthe certain concentration is 0.01 μM, 0.05 μM, 1 μM, 2 μM, 5 μM, 10 μM,15 μM, 20 μM, 25 μM, 50 μM, 75 μM, 100 μM, or 150 μM. In otherembodiments described herein, the cell(s) is contacted or cultured withcertain concentration of a compound of Formula (I) or a form thereof, ora tissue sample is contacted with a certain concentration of a compoundof Formula (I) or a form thereof, wherein the certain concentration is175 μM, 200 μM, 250 μM, 275 μM, 300 μM, 350 μM, 400 μM, 450 μM, 500 μM,550 μM 600 μM, 650 μM, 700 μM, 750 μM, 800 μM, 850 μM, 900 μM, 950 μM or1 mM. In some embodiments described herein, the cell(s) is contacted orcultured with certain concentration of a compound of Formula (I) or aform thereof, or a tissue sample is contacted with a certainconcentration of a compound of Formula (I) or a form thereof, whereinthe certain concentration is 5 nM, 10 nM, 20 nM, 30 nM, 40 nM, 50 nM, 60nM, 70 nM, 80 nM, 90 nM, 100 nM, 150 nM, 200 nM, 250 nM, 300 nM, 350 nM,400 nM, 450 nM, 500 nM, 550 nM, 600 nM, 650 nM, 700 nM, 750 nM, 800 nM,850 nM, 900 nM, or 950 nM. In certain embodiments described herein, thecell(s) is contacted or cultured with certain concentration of acompound of Formula (I) or a form thereof, or a tissue sample iscontacted with a certain concentration of a compound of Formula (I) or aform thereof, wherein the certain concentration is between 0.01 μM to0.1 μM, 0.1 μM to 1 μM, 1 μM to 50 μM, 50 μM to 100 μM, 100 μM to 500μM, 500 μM to 1 nM, 1 nM to 10 nM, 10 nM to 50 nM, 50 nM to 100 nM, 100nM to 500 nM, 500 nM to 1000 nM.

In another embodiment, provided herein is a method for determiningwhether a compound of Formula (I) or a form thereof modulates the amountof an RNA transcript (e.g., an mRNA transcript), comprising: (a)administering a compound of Formula (I) or a form thereof to a subject(in certain embodiments, a non-human animal); and (b) determining theamount of the RNA transcript in a sample obtained from the subject,wherein an alteration in the amount of the RNA transcript measured inthe sample from the subject administered the compound or form thereofrelative to the amount of the RNA transcript in a sample from thesubject prior to administration of the compound or form thereof or asample from a different subject from the same species not administeredthe compound or form thereof indicates that the compound of Formula (I)or a form thereof modulates the amount of the RNA transcript. In anotherembodiment, provided herein is a method for determining whether acompound of Formula (I) or a form thereof modulates the amount of an RNAtranscript (e.g., an mRNA transcript), comprising: (a) administering acompound of Formula (I) or a form thereof to a first subject (in certainembodiments, a non-human animal); (b) administering a negative control(e.g., a pharmaceutical carrier) to a second subject (in certainembodiments, a non-human animal) of the same species as the firstsubject; and (c) determining the amount of the RNA transcript in a firsttissue sample from the first subject and the amount of the RNAtranscript in the second tissue sample from the second subject; and (d)comparing the amount of the RNA transcript in the first tissue sample tothe amount of the RNA transcript in the second tissue sample, wherein analteration in the amount of the RNA transcript in the first tissuesample relative to the amount of the RNA transcript in the second tissuesample indicates that the compound of Formula (I) or a form thereofmodulates the amount of the RNA transcript. In certain embodiments, acompound of Formula (I) or form thereof is administered to a subject ata dose of about 0.001 mg/kg/day to about 500 mg/kg/day. In someembodiments, a single dose of a compound of Formula (I) or a formthereof is administered to a subject in accordance with the methodsdescribed herein. In other embodiments, 2, 3, 4, 5 or more doses of acompound of Formula (I) is administered to a subject in accordance withthe methods described herein. In specific embodiments, the compound ofFormula (I) or a form thereof is administered in a subject in apharmaceutically acceptable carrier, excipient or diluent.

In another embodiment, provided herein is a method for determiningwhether a compound of Formula (I) or a form thereof modulates thesplicing of an RNA transcript (e.g., an mRNA transcript), comprising:(a) administering a compound of Formula (I) or a form thereof to asubject (in certain embodiments, a non-human animal); and (b)determining the amount of two or more RNA transcript splice variants ina sample obtained from the subject, wherein an alteration in the amountof the two or more RNA transcript splice variants measured in the samplefrom the subject administered the compound or form thereof relative tothe amount of the two or more RNA transcript splice variants in a samplefrom the subject prior to administration of the compound or form thereofor a sample from a different subject from the same species notadministered the compound or form thereof indicates that the compound ofFormula (I) or a form thereof modulates the splicing of the RNAtranscript. In another embodiment, provided herein is a method fordetermining whether a compound of Formula (I) or a form thereofmodulates the splicing of an RNA transcript (e.g., an mRNA transcript),comprising: (a) administering a compound of Formula (I) or a formthereof to a first subject (in certain embodiments, a non-human animal);(b) administering a negative control (e.g., a pharmaceutical carrier) toa second subject (in certain embodiments, a non-human animal) of thesame species as the first subject; and (c) determining the amount of twoor more RNA transcript splice variants in a first tissue sample from thefirst subject and the amount of two or more RNA transcript splicevariants in the second tissue sample from the second subject; and (d)comparing the amount of the two or more RNA transcript splice variantsin the first tissue sample to the amount of the two or more RNAtranscript splice variants in the second tissue sample, wherein analteration in the amount of the two or more RNA transcript splicevariants in the first tissue sample relative to the amount of the two ormore RNA transcript splice variants in the second tissue sampleindicates that the compound of Formula (I) or a form thereof modulatesthe splicing of the RNA transcript. In certain embodiments, a compoundof Formula (I) or form thereof is administered to a subject at a dose ofabout 0.001 mg/kg/day to about 500 mg/kg/day. In some embodiments, asingle dose of a compound of Formula (I) or a form thereof isadministered to a subject in accordance with the methods describedherein. In other embodiments, 2, 3, 4, 5 or more doses of a compound ofFormula (I) is administered to a subject in accordance with the methodsdescribed herein. In specific embodiments, the compound of Formula (I)or a form thereof is administered in a subject in a pharmaceuticallyacceptable carrier, excipient or diluent.

In some embodiments, the compound of Formula (I) or a form thereof thatis contacted or cultured with a cell(s) or a tissue sample, oradministered to a subject is a compound of Formula (II), Formula (III),Formula (IV), Formula (V), Formula (VI), Formula (VII), Formula (VIII),Formula (IX), Formula (X), Formula (XI), Formula (XII), Formula (XIII),or Formula (XIV). In some embodiments, the compound of Formula (I) or aform thereof that is contacted or cultured with a cell(s) or a tissuesample, or administered to a subject is a compound described herein.

Techniques known to one skilled in the art may be used to determine theamount of an RNA transcript(s). In some embodiments, the amount of one,two, three or more RNA transcripts is measured using deep sequencing,such as ILLUMINA® RNASeq, ILLUMINA® next generation sequencing (NGS),ION TORRENT™ RNA next generation sequencing, 454™ pyrosequencing, orSequencing by Oligo Ligation Detection (SOLID™). In other embodiments,the amount of multiple RNA transcripts is measured using an exon array,such as the GENECHIP® human exon array. In certain embodiments, theamount of one, two, three or more RNA transcripts is determined byRT-PCR. In other embodiments, the amount of one, two, three or more RNAtranscripts is measured by RT-qPCR. Techniques for conducting theseassays are known to one skilled in the art.

In some embodiments, a statistical analysis or other analysis isperformed on data from the assay utilized to measure an RNA transcript.In certain embodiments, a student t-test statistical analysis isperformed on data from the assay utilized to measure an RNA transcriptto determined those RNA transcripts that have an alternation in amountin the presence of the compound relative to the amount in the absence ofthe compound or presence of a negative control. In specific embodiments,the student t-test value of those RNA transcripts with the alternationis 10%, 5%, 4%, 3%, 2%, 1%, 0.5% or 0.1%. In some specific embodiments,p value of those RNA transcripts with the alternation is 10%, 5%, 4%,3%, 2%, 1%, 0.5% or 0.1%. In certain specific embodiments, the studentt-test and p values of those RNA transcripts with the alteration are10%, 5%, 4%, 3%, 2%, 1%, 0.5% or 0.1% and 10%, 5%, 4%, 3%, 2%, 1%, 0.5%or 0.1%, respectively.

In certain embodiments, a further analysis is performed to determine howthe compound of Formula (I) or a form thereof is changing the amount ofan RNA transcript(s). In specific embodiments, a further analysis isperformed to determine if an alternation in the amount of an RNAtranscript(s) in the presence of a compound of Formula (I) or a formthereof relative the amount of the RNA transcript(s) in the absence ofthe compound or a form thereof, or the presence of a negative control isdue to changes in transcription, splicing, and/or stability of the RNAtranscript(s). Techniques known to one skilled in the art may be used todetermine whether a compound of Formula (I) or a form thereof changes,e.g., the transcription, splicing and/or stability of an RNAtranscript(s).

In certain embodiments, the stability of one or more RNA transcripts isdetermined by serial analysis of gene expression (SAGE), differentialdisplay analysis (DD), RNA arbitrarily primer (RAP)-PCR, restrictionendonuclease-lytic analysis of differentially expressed sequences(READS), amplified restriction fragment-length polymorphism (ALFP),total gene expression analysis (TOGA), RT-PCR, RT-qPCR, high-densitycDNA filter hybridization analysis (HDFCA), suppression subtractivehybridization (SSH), differential screening (DS), cDNA arrays,oligonucleotide chips, or tissue microarrays. In other embodiments, thestability of one or more RNA transcripts is determined by Northernblots, RNase protection, or slot blots.

In some embodiments, the transcription in a cell(s) or tissue sample isinhibited before (e.g., 5 minutes, 10 minutes, 30 minutes, 1 hour, 2hours, 4 hours, 6 hours, 8 hours, 12 hours, 18 hours, 24 hours, 36hours, 48 hours, or 72 hours before) or after (e.g., 5 minutes, 10minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12hours, 18 hours, 24 hours, 36 hours, 48 hours, or 72 hours after) thecell or the tissue sample is contacted or cultured with an inhibitor oftranscription, such as α-amanitin, DRB, flavopiridol, triptolide, oractinomycin-D. In other embodiments, the transcription in a cell(s) ortissue sample is inhibited with an inhibitor of transcription, such asα-amanitin, DRB, flavopiridol, triptolide, or actinomycin-D, while thecell(s) or tissue sample is contacted or cultured with a compound ofFormula (I) or a form thereof.

In certain embodiments, the level of transcription of one or more RNAtranscripts is determined by nuclear run-on assay or an in vitrotranscription initiation and elongation assay. In some embodiments, thedetection of transcription is based on measuring radioactivity orfluorescence. In some embodiments, a PCR-based amplification step isused.

In specific embodiments, the amount of alternatively spliced forms ofthe RNA transcripts of a particular gene are measured to see if there isan alteration in the amount of one, two or more alternatively splicedforms of the RNA transcripts of the gene. In some embodiments, theamount of an isoform(s) encoded by a particular gene is measured to seeif there is an alteration in the amount of the isoform(s). In certainembodiments, the levels of spliced forms of RNA are quantified byRT-PCR, RT-qPCR, or northern blotting. In other embodiments,sequence-specific techniques may be used to detect the levels of anindividual spliceoform. In certain embodiments, splicing is measured invitro using nuclear extracts. In some embodiments, detection is based onmeasuring radioactivity or fluorescence. Techniques known to one skilledin the art may be used to measure alterations in the amount ofalternatively spliced forms of an RNA transcript of a gene andalterations in the amount of an isoform encoded by a gene.

Pharmaceutical Compositions and Modes of Administration

When administered to a patient, a compound of Formula (I) or a formthereof is preferably administered as a component of a composition thatoptionally comprises a pharmaceutically acceptable carrier, excipient ordiluent. The composition can be administered orally, or by any otherconvenient route, for example, by infusion or bolus injection, byabsorption through epithelial or mucocutaneous linings (e.g., oralmucosa, rectal, and intestinal mucosa) and may be administered togetherwith another biologically active agent. Administration can be systemicor local. Various delivery systems are known, e.g., encapsulation inliposomes, microparticles, microcapsules, capsules, and can be used toadminister the compound.

Methods of administration include, but are not limited to, parenteral,intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous,intranasal, epidural, oral, sublingual, intranasal, intraocular,intratumoral, intracerebral, intravaginal, transdermal, ocularly,rectally, by inhalation, or topically, particularly to the ears, nose,eyes, or skin. The mode of administration is left to the discretion ofthe practitioner. In most instances, administration will result in therelease of a compound into the bloodstream, tissue or cell(s). In aspecific embodiment, a compound is administered orally.

The amount of a compound of Formula (I) or a form thereof that will beeffective in the treatment of a disease resulting from an aberrantamount of mRNA transcripts depends, e.g., on the route ofadministration, the disease being treated, the general health of thesubject, ethnicity, age, weight, and gender of the subject, diet, time,and the severity of disease progress, and should be decided according tothe judgment of the practitioner and each patient's or subject'scircumstances.

In specific embodiments, an “effective amount” in the context of theadministration of a compound of Formula (I) or a form thereof, orcomposition or medicament thereof refers to an amount of a compound ofFormula (I) or a form thereof to a patient which has a therapeuticeffect and/or beneficial effect. In certain specific embodiments, an“effective amount” in the context of the administration of a compound ofFormula (I) or a form thereof, or composition or medicament thereof to apatient results in one, two or more of the following effects: (i)reduces or ameliorates the severity of a disease; (ii) delays onset of adisease; (iii) inhibits the progression of a disease; (iv) reduceshospitalization of a subject; (v) reduces hospitalization length for asubject; (vi) increases the survival of a subject; (vii) improves thequality of life of a subject; (viii) reduces the number of symptomsassociated with a disease; (ix) reduces or ameliorates the severity of asymptom(s) associated with a disease; (x) reduces the duration of asymptom associated with a disease associated; (xi) prevents therecurrence of a symptom associated with a disease; (xii) inhibits thedevelopment or onset of a symptom of a disease; and/or (xiii) inhibitsof the progression of a symptom associated with a disease. In certainembodiments, an effective amount of a compound of Formula (I) or a formthereof is an amount effective to restore the amount of a RNA transcriptof a gene to the amount of the RNA transcript detectable in healthypatients or cells from healthy patients. In other embodiments, aneffective amount of a compound of Formula (I) or a form thereof is anamount effective to restore the amount an RNA isoform and/or proteinisoform of gene to the amount of the RNA isoform and/or protein isoformdetectable in healthy patients or cells from healthy patients.

In certain embodiments, an effective amount of a compound of Formula (I)or a form thereof is an amount effective to decrease the aberrant amountof an RNA transcript of a gene which associated with a disease. Incertain embodiments, an effective amount of a compound of Formula (I) ora form thereof is an amount effective to decrease the amount of theaberrant expression of an isoform of a gene. In some embodiments, aneffective amount of a compound of Formula (I) or a form thereof is anamount effective to result in a substantial change in the amount of anRNA transcript (e.g., mRNA transcript), alternative splice variant orisoform.

In certain embodiments, an effective amount of a compound of Formula (I)or a form thereof is an amount effective to increase or decrease theamount of an RNA transcript (e.g., an mRNA transcript) of gene which isbeneficial for the prevention and/or treatment of a disease. In certainembodiments, an effective amount of a compound of Formula (I) or a formthereof is an amount effective to increase or decrease the amount of analternative splice variant of an RNA transcript of gene which isbeneficial for the prevention and/or treatment of a disease. In certainembodiments, an effective amount of a compound of Formula (I) or a formthereof is an amount effective to increase or decrease the amount of anisoform of gene which is beneficial for the prevention and/or treatmentof a disease. Non-limiting examples of effective amounts of a compoundof Formula (I) or a form thereof are described herein.

For example, the effective amount may be the amount required to preventand/or treat a disease associated with the aberrant amount of an mRNAtranscript of gene in a human subject.

In general, the effective amount will be in a range of from about 0.001mg/kg/day to about 500 mg/kg/day for a patient having a weight in arange of between about 1 kg to about 200 kg. The typical adult subjectis expected to have a median weight in a range of between about 70 andabout 100 kg.

Within the scope of the present description, the “effective amount” of acompound of Formula (I) or a form thereof for use in the manufacture ofa medicament, the preparation of a pharmaceutical kit or in a method forpreventing and/or treating a disease in a human subject in need thereof,is intended to include an amount in a range of from about 0.001 mg toabout 35,000 mg.

The compositions described herein are formulated for administration tothe subject via any drug delivery route known in the art. Non-limitingexamples include oral, ocular, rectal, buccal, topical, nasal,ophthalmic, subcutaneous, intramuscular, intraveneous (bolus andinfusion), intracerebral, transdermal, and pulmonary routes ofadministration.

Embodiments described herein include the use of a compound of Formula(I) or a form thereof in a pharmaceutical composition. In a specificembodiment, described herein is the use of a compound of Formula (I) ora form thereof in a pharmaceutical composition for preventing and/ortreating a disease in a human subject in need thereof comprisingadministering an effective amount of a compound of Formula (I) or a formthereof in admixture with a pharmaceutically acceptable carrier,excipient or diluent. In a specific embodiment, the human subject is apatient with a disease associated with the aberrant amount of an mRNAtranscript(s).

A compound of Formula (I) or a form thereof may optionally be in theform of a composition comprising the compound or a form thereof and anoptional carrier, excipient or diluent. Other embodiments providedherein include pharmaceutical compositions comprising an effectiveamount of a compound of Formula (I) or a form thereof and apharmaceutically acceptable carrier, excipient, or diluent. In aspecific embodiment, the pharmaceutical compositions are suitable forveterinary and/or human administration. The pharmaceutical compositionsprovided herein can be in any form that allows for the composition to beadministered to a subject.

In a specific embodiment and in this context, the term “pharmaceuticallyacceptable carrier, excipient or diluent” means a carrier, excipient ordiluent approved by a regulatory agency of the Federal or a stategovernment or listed in the U.S. Pharmacopeia or other generallyrecognized pharmacopeia for use in animals, and more particularly inhumans. The term “carrier” refers to a diluent, adjuvant (e.g., Freund'sadjuvant (complete and incomplete)), excipient, or vehicle with which atherapeutic agent is administered. Such pharmaceutical carriers can besterile liquids, such as water and oils, including those of petroleum,animal, vegetable or synthetic origin, such as peanut oil, soybean oil,mineral oil, sesame oil and the like. Water is a specific carrier forintravenously administered pharmaceutical compositions. Saline solutionsand aqueous dextrose and glycerol solutions can also be employed asliquid carriers, particularly for injectable solutions.

Typical compositions and dosage forms comprise one or more excipients.Suitable excipients are well-known to those skilled in the art ofpharmacy, and non limiting examples of suitable excipients includestarch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk,silica gel, sodium stearate, glycerol monostearate, talc, sodiumchloride, dried skim milk, glycerol, propylene, glycol, water, ethanoland the like. Whether a particular excipient is suitable forincorporation into a pharmaceutical composition or dosage form dependson a variety of factors well known in the art including, but not limitedto, the way in which the dosage form will be administered to a patientand the specific active ingredients in the dosage form. Further providedherein are anhydrous pharmaceutical compositions and dosage formscomprising one or more compounds of Formula (I) or a form thereof asdescribed herein. The compositions and single unit dosage forms can takethe form of solutions or syrups (optionally with a flavoring agent),suspensions (optionally with a flavoring agent), emulsions, tablets(e.g., chewable tablets), pills, capsules, granules, powder (optionallyfor reconstitution), taste-masked or sustained-release formulations andthe like.

Pharmaceutical compositions provided herein that are suitable for oraladministration can be presented as discrete dosage forms, such as, butare not limited to, tablets, caplets, capsules, granules, powder, andliquids. Such dosage forms contain predetermined amounts of activeingredients, and may be prepared by methods of pharmacy well known tothose skilled in the art.

Examples of excipients that can be used in oral dosage forms providedherein include, but are not limited to, binders, fillers, disintegrants,and lubricants.

Methods of Modulating the Amount of RNA Transcripts Encoded by CertainGenes

In one aspect, described herein are methods for modulating the amount ofa product of a gene, wherein a precursor RNA transcript transcribed fromthe gene contains a REMS, and the methods utilize a compound describedherein. In certain embodiments, the gene is any one of the genesdisclosed in Tables 1-4 or 6. In certain embodiments, the gene containsa nucleotide sequence encoding a non-endogenous REMS. In one embodiment,provided herein are methods for modulating the amount of one, two, threeor more RNA transcripts of a gene, by way of nonlimiting example,disclosed in Table 6, infra, the method comprising contacting a cellwith a compound of Formula (I) or a form thereof.

In another embodiment, provided herein are methods for modulating theamount of one, two, three or more RNA transcripts of a gene, notdisclosed in Tables 1-4, infra, wherein the precursor transcripttranscribed from the gene comprises a REMS, the method comprisingcontacting a cell with a compound of Formula (I) or a form thereof.

In another embodiment, provided herein are methods for modulating theamount of one, two, three or more RNA transcripts of a gene, notdisclosed in International Patent Application No. PCT/US2014/071252(International Publication No. WO 2015/105657 A1), wherein the precursortranscript transcribed from the gene comprises a REMS, the methodcomprising contacting a cell with a compound of Formula (I) or a formthereof.

In another embodiment, provided herein are methods for modulating theamount of one, two, three or more RNA transcripts of a gene, notdisclosed in Table 6, infra, wherein the precursor transcripttranscribed from the gene comprises a REMS, the method comprisingcontacting a cell with a compound of Formula (I) or a form thereof.

In another embodiment, provided herein are methods for modulating theamount of one, two, three or more RNA transcripts of ERGIC3, comprisingcontacting a cell with a compound of Formula (I) or a form thereof. Seethe example section for additional information regarding the genes inTable 6. In certain embodiments, the cell is contacted with the compoundof Formula (I) or a form thereof in a cell culture. In otherembodiments, the cell is contacted with the compound of Formula (I) or aform thereof in a subject (e.g., a non-human animal subject or a humansubject).

In certain embodiments, the cell(s) contacted or cultured with acompound of Formula (I) or a form thereof is primary cell(s) or cell(s)from a cell line. In some embodiments, the cell(s) contacted or culturedwith a compound of Formula (I) or a form thereof is a fibroblast(s), animmune cell(s), or a muscle cell(s). In some embodiments, the cell(s)contacted or cultured with a compound of Formula (I) or a form thereofis a cancer cell. Non-limiting examples of cell lines include 293, 3T3,4T1, 721, 9L, A2780, A172, A20, A253, A431, A-549, ALC, B16, B35, BCP-1,BEAS-2B, bEnd.3, BHK, BR 293, BT2O, BT483, BxPC3, C2C12, C3H-10T1/2,C6/36, C6, Cal-27, CHO, COR-L23, COS, COV-434, CML T1, CMT, CRL7O3O,CT26, D17, DH82, DU145, DuCaP, EL4, EM2, EM3, EMT6, FM3, H1299, H69,HB54, HB55, HCA2, HEK-293, HeLa, Hepa1c1c7, HL-60, HMEC, Hs578T,HsS78Bst, HT-29, HTB2, HUVEC, Jurkat, J558L, JY, K562, Ku812, KCL22,KG1, KYO1, LNCap, Ma-Mel, MC-38, MCF-7, MCF-10A, MDA-MB-231, MDA-MB-468,MDA-MB-435, MDCK, MG63, MOR/0.2R, MONO-MAC 6, MRC5, MTD-1A, NCI-H69,NIH-3T3, NALM-1, NS0, NW-145, OPCN, OPCT, PNT-1A, PNT-2, Raji, RBL,RenCa, RIN-5F, RMA, Saos-2, Sf21, Sf9, SiHa, SKBR3, SKOV-3, T2, T-47D,T84, THP1, U373, U87, U937, VCaP, Vero, VERY, W138, WM39, WT-49, X63,YAC-1, and YAR cells. In one embodiment, the cells are from a patient.

In certain embodiments described herein, the cell(s) is contacted orcultured with a compound of Formula (I) or a form thereof with acompound of Formula (I) or a form thereof for a period of 15 minutes, 30minutes, 45 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6hours, 8 hours, 12 hours, 18 hours, 24 hours, 48 hours, 72 hours ormore. In other embodiments described herein, the cell(s) is contacted orcultured with a compound of Formula (I) or a form thereof with acompound of Formula (I) or a form thereof for a period of 15 minutes to1 hour, 1 to 2 hours, 2 to 4 hours, 6 to 12 hours, 12 to 18 hours, 12 to24 hours, 28 to 24 hours, 24 to 48 hours, 48 to 72 hours.

In certain embodiments described herein, the cell(s) is contacted orcultured with certain concentration of a compound of Formula (I) or aform thereof, wherein the certain concentration is 0.01 μM, 0.05 μM, 1μM, 2 μM, 5 μM, 10 μM, 15 μM, 20 μM, 25 μM, 50 μM, 75 μM, 100 μM, or 150μM. In other embodiments described herein, the cell(s) is contacted orcultured with certain concentration of a compound of Formula (I) or aform thereof, wherein the certain concentration is 175 μM, 200 μM, 250μM, 275 μM, 300 μM, 350 μM, 400 μM, 450 μM, 500 μM, 550 μM 600 μM, 650μM, 700 μM, 750 μM, 800 μM, 850 μM, 900 μM, 950 μM or 1 mM. In someembodiments described herein, the cell(s) is contacted or cultured withcertain concentration of a compound of Formula (I) or a form thereof,wherein the certain concentration is 5 nM, 10 nM, 20 nM, 30 nM, 40 nM,50 nM, 60 nM, 70 nM, 80 nM, 90 nM, 100 nM, 150 nM, 200 nM, 250 nM, 300nM, 350 nM, 400 nM, 450 nM, 500 nM, 550 nM, 600 nM, 650 nM, 700 nM, 750nM, 800 nM, 850 nM, 900 nM, or 950 nM. In certain embodiments describedherein, the cell(s) is contacted or cultured with certain concentrationof a compound of Formula (I) or a form thereof, wherein the certainconcentration is between 0.01 μM to 0.1 μM, 0.1 μM to 1 μM, 1 μM to 50μM, 50 μM to 100 μM, 100 μM to 500 μM, 500 μM to 1 nM, 1 nM to 10 nM, 10nM to 50 nM, 50 nM to 100 nM, 100 nM to 500 nM, 500 nM to 1000 nM. Incertain embodiments described herein, the cell(s) is contacted orcultured with certain concentration of a compound of Formula (I) or aform thereof that results in a substantial change in the amount of anRNA transcript (e.g., an mRNA transcript), an alternatively splicedvariant, or an isoform of a gene (e.g., a gene in Table 6, infra).

In another aspect, provided herein are methods for modulating the amountof one, two, three or more RNA transcripts of a gene, wherein theprecursor RNA transcript transcribed from the gene comprises a REMS, themethods comprising administering to a patient in need thereof a compoundof Formula (I) or a form thereof, or a pharmaceutical compositioncomprising a compound of Formula (I) or a form thereof and apharmaceutically acceptable carrier, excipient or diluent.

In one embodiment, provided herein are methods for modulating the amountof one, two, three or more RNA transcripts of a gene, by way ofnonlimiting example, disclosed in Table 6, infra, the methods comprisingadministering to a patient in need thereof a compound of Formula (I) ora form thereof, or a pharmaceutical composition comprising a compound ofFormula (I) or a form thereof and a pharmaceutically acceptable carrier,excipient or diluent.

In another embodiment, provided herein are methods for modulating theamount of one, two, three or more RNA transcripts of a gene, notdisclosed in Tables 1-4, infra, wherein the precursor RNA transcripttranscribed from the gene comprises a REMS, the methods comprisingadministering to a patient in need thereof a compound of Formula (I) ora form thereof, or a pharmaceutical composition comprising a compound ofFormula (I) or a form thereof and a pharmaceutically acceptable carrier,excipient or diluent.

In another embodiment, provided herein are methods for modulating theamount of one, two, three or more RNA transcripts of a gene in asubject, not disclosed in International Patent Application No.PCT/US2014/071252 (International Publication No. WO 2015/105657 A1),wherein the precursor RNA transcript transcribed from the gene comprisesa REMS, the methods comprising administering to the subject a compoundof Formula (I) or a form thereof, or a pharmaceutical compositioncomprising a compound of Formula (I) or a form thereof and apharmaceutically acceptable carrier, excipient or diluent.

In another embodiment, provided herein are methods for modulating theamount of one, two, three or more RNA transcripts of a gene, notdisclosed in International Patent Application No. PCT/US2014/071252(International Publication No. WO 2015/105657 A1), wherein the precursorRNA transcript transcribed from the gene comprises a REMS, the methodscomprising administering a patient in need thereof a compound of Formula(I) or a form thereof, or a pharmaceutical composition comprising acompound of Formula (I) or a form thereof and a pharmaceuticallyacceptable carrier, excipient or diluent.

In a particular aspect, provided herein are methods for modulating theamount of one, two, three or more RNA transcripts of a gene in asubject, wherein the precursor RNA transcript transcribed from the genecomprises a REMS (for example, an endogenous REMS or a non-endogenousREMS), the methods comprising administering to the subject a compound ofFormula (I) or a form thereof, or a pharmaceutical compositioncomprising a compound of Formula (I) or a form thereof and apharmaceutically acceptable carrier, excipient or diluent, wherein thegene is: ABCA1, ABCB7, ABCC1, ABHD10, ABL2, ABLIM3, ACACA, ACADVL,ACAT2, ADAM12, ADAM15, ADAM17, ADAM33, AFF2, AGK, AGPAT3, AGPS, AHCYL2,AHDC1, AHRR, AJUBA, AK021888, AK310472, AKAP1, AKAP9, AKNA, ALCAM,ALDH4A1, AMPD2, ANK2, ANKFY1, ANKHD1-EIF4EBP3, ANKRD17, ANKS6, ANP32A,ANXA11, ANXA6, AP2B1, APAF1, APLP2, APP, APPL2, APTX, ARHGAP22, ARID1A,ARID2, ARMCX3, ASAP1, ASL, ASNS, ASPH, ATAD2B, ATF7IP, ATG9A, ATMIN,ATP2C1, ATXN3, AURKA, AXIN1, B4GALT2, BACE1, BAG2, BASP1, BC033281,BCAR3, BEND6, BICD1, BIN1, BNC1, BRD2, BRPF1, BSCL2, BTBD10, BZW1,C11orf30, C11orf73, C17orf76-AS1, C4orf27, C5orf24, C6orf48, C9orf69,CAB39, CALU, CAMKK1, CAPNS1, CASC3, CASP8AP2, CAV1, CCAR1, CCDC77,CCDC88A, CCDC92, CCT6A, CD276, CD46, CDC25B, CDC40, CDC₄₂BPA, CDCA7,CDH11, CDH13, CDK11B, CDK16, CDKAL1, CEP68, CFLAR, CHD8, CIZ1, CLIC1,CLK4, CNOT1, COG1, COL12A1, COL1A1, COL6A1, COPS7B, CPEB2, CREB5, CRLS1,CRTAP, CSDE1, CSNK1A1, CTDSP2, CTNND1, CUL2, CUL4A, CUX1, CYB5B, CYBRD1,CYP51A1, DAB2, DACT1, DARS, DAXX, DCAF10, DCAF11, DCBLD2, DCUN1D4,DDAH1, DDAH2, DDHD2, DDR1, DDX39B, DDX42, DENND1A, DENND1B, DENND5A,DGCR2, DGKA, DHCR24, DHCR7, DHFR, DHX9, DIAPH1, DIAPH3, DIS3L,DKFZp434M1735, DKK3, DLC1, DNM2, DOCK1, DPP8, DSEL, DST, DSTN, EBF1,EEA1, EEF1A1, EFCAB14, EGR1, EHMT2, EIF2B3, EIF4G1, EIF4G2, EIF4G3,ELF2, ENG, ENPP2, ENSA, EPN1, EPT1, ERC1, ERGIC3, ETV5, EXO1, EXTL2,EYA3, FADS1, FADS2, FAF1, FAM111A, FAM198B, FAM219A, FAM219B, FAM3C,FAM65A, FBXO10, FBXO18, FBXO31, FBXO34, FBXO9, FDFT1, FDPS, FER, FEZ1,FGD5-AS1, FGFRL1, FHOD3, FLII, FLNB, FN1, FNBP1, FOCAD, FOS, FOSB,FOSL1, FOXK1, FOXM1, FUS, FYN, GABPB1, GALC, GALNT1, GAS7, GBA2, GCFC2,GGCT, GHDC, GIGYF2, GJC1, GMIP, GNA13, GNAS, GNL3L, GOLGA2, GOLGA4,GOLGB1, GORASP1, GPR1, GPR89A, GPSM2, GREM1, GRK6, GSE1, GTF2H2B, HAS2,HAT1, HAUS3, HAUS6, HDAC7, HEG1, HLA-A, HLA-E, HLTF, HMGA1, HMGB1,HMGCR, HMGCS1, HMOX1, HNRNPR, HNRNPUL1, HP1BP3, HRH1, HSD17B12, HSD17B4,HTT, IARS, IDH1, IDI1, IGF2BP2, IL6ST, INHBA, INSIG1, IQCE, ITGAV,ITGB5, ITM2C, ITSN1, KANSL3, KCNK2, KIAA1033, KIAA1143, KIAA1199,KIAA1522, KIAA1524, KIAA1549, KIAA1715, KIF14, KIF2A, KIF3A, KLC1, KLC2,KLF6, KLHL7, KRT18, KRT19, KRT34, KRTAP2-3, LAMA2, LAMB1, LARP4, LARP7,LATS2, LDLR, LEMD3, LGALS8, LIMS1, LINC00341, LINC00657, LMAN2L, LMO7,LONP1, LOX, LRCH4, LRIG1, LRP8, LRRC8A, LSS, LTBR, LUC7L2, LZTS2, MADD,MAGED4, MAGED4B, MAN1A2, MAP4K4, MBD1, MBOAT7, MDM2, MED1, MEDAG, MEF2D,MEIS2, MEMO1, MEPCE, MFGE8, MICAL2, MINPP1, MKL1, MKLN1, MKNK2, MLLT4,MLST8, MMAB, MMS19, MMS22L, MPPE1, MPZL1, MRPL3, MSANTD3, MSC, MSH2,MSH6, MSL3, MSMO1, MSRB3, MTAP, MTERFD1, MTHFD1L, MTMR9, MTRR, MUM1,MVD, MVK, MYADM, MYLK, MYO1D, MYO9B, MYOF, NAA35, NADK, NASP, NAV1,NAV2, NCOA1, NCOA3, NCOA4, NCSTN, NELFA, NEO1, NEURL1B, NF2, NFE2L1,NFX1, NID1, NID2, NIPA1, NKX3-1, NOL10, NOMO3, NPEPPS, NRD1, NREP, NRG1,NSUN4, NT5C2, NT5E, NTNG1, NUDT4, NUP153, NUP35, NUP50, NUPL1, NUSAP1,ODF2, OS9, OSBPL6, OSMR, P4HA1, P4HB, PABPC1, PAK4, PAPD4, PARD3, PARN,PARP14, PARP4, PARVB, PCBP2, PCBP4, PCDHGB3, PCGF3, PCM1, PCMTD2,PCNXL2, PCSK9, PDE4A, PDE7A, PDLIM7, PDXDC1, PEPD, PEX5, PFKP, PHF19,PHF8, PHRF1, PHTF2, PI4K2A, PIEZO1, PIGU, PIK3C2B, PITPNA, PITPNB,PITPNM1, PLAU, PLEC, PLEKHB2, PLSCR3, PLXNB2, PLXNC1, PMS1, POLE3,POLR3D, POSTN, POU2F1, PPAPDC1A, PPARA, PPHLN1, PPIP5K1, PPP1R12A,PPP6R1, PPP6R2, PRKACB, PRKDC, PRMT1, PRNP, PRSS23, PSMA4, PSMC1, PSMD6,PTK2B, PTPN14, PUF60, PUS7, PVR, PXN, QKI, RAB23, RAB2B, RAB34, RAD1,RAD23B, RALB, RAP1A, RAP1GDS1, RARG, RASSF8, RBCK1, RBFOX2, RBM10, RCC1,RFTN1, RFWD2, RGS10, RGS3, RIF1, RNF14, RNF19A, RNF38, RNFT1, RPL10,RPS6KC1, RRBP1, RWDD4, SAMD9, SAMD9L, SAR1A, SART3, SCAF4, SCAF8, SCD,SCLT1, SCO1, SDCBP, SEC14L1, SEC22A, SEC24B, SEC61A1, SEPT9, SERPINE2,SF1, SGOL2, SH3RF1, SKIL, SLC25A17, SLC39A3, SLC41A1, SLC4A4, SLC7A6,SLC7A8, SMARCA4, SMARCC2, SMC4, SMC6, SMCHD1, SMG1, SMN2, SMPD4, SMYD3,SMYD5, SNAP23, SNHG16, SNX14, SOCS2, SON, SOS2, SPATA20, SPATS2, SPG20,SPRED2, SQLE, SQRDL, SQSTM1, SRCAP, SREBF1, SREK1, SRSF3, STARD4, STAT1,STAT3, STAU1, STC2, STEAP2, STRIP1, STRN3, STX16, SUPT20H, SYNE1, SYNE2,SYT15, SYTL2, TACC1, TAF2, TANC2, TARBP1, TARS, TBC1D15, TBL2, TCF7L2,TENC1, TENM2, TEP1, TET3, TFCP2, TGFBI, TGFBR1, TGFBRAP1, THADA, THAP4,THRB, TIMP2, TJP2, TLE3, TLK1, TMEM154, TMEM47, TMEM63A, TNC, TNFAIP3,TNFRSF12A, TNIP1, TNKS1BP1, TNPO3, TNS1, TNS3, TOE1, TOMM40, TOMM5,TOPORS, TP53INP1, TRAF3, TRAK1, TRAPPC12, TRIB1, TRIM2, TRIM23, TRIM26,TRIM28, TRIM65, TRMT1L, TRPS1, TSC2, TSHZ1, TSPAN2, TTC7A, TUBB2C,TUBB3, TXNL1, TXNRD1, U2SURP, UBAP2L, UBE2G2, UBE2V1, UBQLN4, UCHL5,UHMK1, UHRF1BPL, UNC5B, USP19, USP7, VANGL1, VARS2, VCL, VIPAS39,VPS13A, VPS29, VPS51, VWA8, WDR19, WDR37, WDR48, WIPF1, WNT5B, WSB1,WWTR1, XIAP, XRN2, YAP1, YES1, YPEL5, YTHDF3, Z24749, ZAK, ZBTB10,ZBTB24, ZBTB7A, ZC3H12C, ZC3H14, ZC3H18, ZCCHC11, ZEB1, ZEB2, ZFAND1,ZFAND5, ZHX3, ZMIZ1, ZMYM2, ZNF12, ZNF148, ZNF219, ZNF227, ZNF24,ZNF268, ZNF28, ZNF281, ZNF335, ZNF37A, ZNF37BP, ZNF395, ZNF583, ZNF621,ZNF652, ZNF655, ZNF674, ZNF74, ZNF764, ZNF778, ZNF780A, ZNF827, ZNF839or ZNF91.

In another particular aspect, provided herein are methods for modulatingthe amount of one, two, three or more RNA transcripts of a gene in asubject, wherein the precursor RNA transcript transcribed from the genecomprises a REMS (for example, an endogenous REMS or a non-endogenousREMS), the methods comprising administering to the subject a compound ofFormula (I) or a form thereof, or a pharmaceutical compositioncomprising a compound of Formula (I) or a form thereof and apharmaceutically acceptable carrier, excipient or diluent, wherein thegene is: SMN2, FOXM1, APLP2, GGCT, ABHD10, STRN3, VPS29, ERGIC3, MADD,LARP 7, ARMCX6, GALC, LAMA2, PRKDC, RCC1, FADS2, DIAPH3, FN1, PARP1,COL1A1, COL1A2, COL3A1 or COL5A2.

In another particular aspect, provided herein are methods for modulatingthe amount of one, two, three or more RNA transcripts of a gene in asubject, wherein the precursor RNA transcript transcribed from the genecomprises a REMS (for example, an endogenous REMS or a non-endogenousREMS), the methods comprising administering to the subject a compound ofFormula (I) or a form thereof, or a pharmaceutical compositioncomprising a compound of Formula (I) or a form thereof and apharmaceutically acceptable carrier, excipient or diluent, wherein thegene is: SMN2, FOXM1, APLP2, GGCT, ABHD10, STRN3, VPS29, ERGIC3, MADD,LARP7 or COL1A1.

In another particular aspect, provided herein are methods for modulatingthe amount of one, two, three or more RNA transcripts of a gene in asubject, wherein the precursor RNA transcript transcribed from the genecomprises a REMS (for example, an endogenous REMS or a non-endogenousREMS), the methods comprising administering to the subject a compound ofFormula (I) or a form thereof, or a pharmaceutical compositioncomprising a compound of Formula (I) or a form thereof and apharmaceutically acceptable carrier, excipient or diluent, wherein thegene is ERGIC3.

In another particular aspect, provided herein are methods for modulatingthe amount of one, two, three or more RNA transcripts of a gene in asubject, wherein the precursor RNA transcript transcribed from the genecomprises a non-endogenous REMS, the methods comprising administering tothe subject a compound of Formula (I) or a form thereof, or apharmaceutical composition comprising a compound of Formula (I) or aform thereof and a pharmaceutically acceptable carrier, excipient ordiluent.

In another embodiment, provided herein are methods for modulating theamount of one, two, three or more RNA transcripts of a gene, notdisclosed in Table 6, infra, wherein the precursor RNA transcripttranscribed from the gene comprises a REMS, the methods comprisingadministering to a patient in need thereof a compound of Formula (I) ora form thereof, or a pharmaceutical composition comprising a compound ofFormula (I) or a form thereof and a pharmaceutically acceptable carrier,excipient or diluent.

In another embodiment, provided herein are methods for modulating theamount of one, two, three or more RNA transcripts of ERGIC3, comprisingadministering to a patient in need thereof a compound of Formula (I) ora form thereof, or a pharmaceutical composition comprising a compound ofFormula (I) or a form thereof and a pharmaceutically acceptable carrier,excipient or diluent. See the example section for additional informationregarding the genes in Table 6.

In certain embodiments, a compound of Formula (I) or a form thereofcontacted or cultured with a cell(s), or administered to a subject is acompound of Formula (II), Formula (III), Formula (IV), Formula (V),Formula (VI), Formula (VII), Formula (VIII), Formula (IX), Formula (X),Formula (XI), Formula (XII), Formula (XIII), or Formula (XIV). In someembodiments, a compound of Formula (I) or a form thereof contacted orcultured with a cell(s), or administered to a subject is a compounddescribed herein.

Table 1 shows 263 genes that, in the presence of Compound 774 (3 □M),demonstrate an effect on isoform fold increase having a statisticallysignificant adjusted p value of at least 0.01.

TABLE 1 ABCA1, ABCC1, ABL2, ACACA, ACAT2, AFF2, AHRR, AK021888,AK310472, AKAP1, ANK2, ANKHD1-EIF4EBP3, AP2B1, APAF1, APLP2, ARID1A,ARMCX3, ASAP1, ASPH, ATAD2B, ATF7IP, ATG9A, AXIN1, BACE1, BIN1, BNC1,BRPF1, BZW1, C11orf30, C11orf73, C17orf76-AS1, C4orf27, C6orf48, CAB39,CAMKK1, CCDC88A, CCDC92, CDC25B, CDC42BPA, CDCA7, CDH11, CDH13, CEP68,CFLAR, COPS7B, CREB5, CUL2, CUL4A, CUX1, CYP51A1, DCUN1D4, DDR1, DDX39B,DDX42, DENND1A, DENND5A, DGKA, DHCR24, DHCR7, DIAPH1, DIAPH3, DNM2,DOCK1, EFCAB14, EIF2B3, EPN1, EPT1, ERC1, ETV5, FADS1, FADS2, FAF1,FAM198B, FAM219B, FBXO10, FBXO9, FDFT1, FDPS, FER, FEZ1, FHOD3, FLIT,FLNB, FNBP1, FOS, FOSB, FOXM1, FYN, GABPB1, GALC, GAS7, GGCT, GJC1,GPSM2, GRK6, HAS2, HAT1, HLTF, HMGA1, HMGB1, HMGCR, HMGCS1, HMOX1,HP1BP3, HSD17B12, HTT, IDI1, INHBA, INSIG1, KANSL3, KIAA1199, KIAA1524,KIAA1715, KIF3A, KLF6, KRT19, KRT34, KRTAP2-3, LAMA2, LARP7, LDLR,LEMD3, LMAN2L, LRCH4, LRP8, LSS, MAGED4, MAGED4B, MAN1A2, MEDAG, MEF2D,MEMO1, MFGE8, MICAL2, MMAB, MMS19, MMS22L, MSL3, MSMO1, MTAP, MTERFD1,MVD, MVK, NASP, NAV2, NEURL1B, NFE2L1, NID1, NPEPPS, NREP, NRG1, NSUN4,NT5C2, NUP153, P4HA1, PABPC1, PAPD4, PCBP2, PCM1, PCSK9, PDXDC1, PEPD,PHF19, PHF8, PHTF2, PIK3C2B, PITPNB, PLEC, PMS1, POU2F1, PPHLN1, PRKDC,PRSS23, PSMC1, PTPN14, PUF60, PVR, RAB23, RAD23B, RAP1A, RASSF8, RBM10,RCC1, RFWD2, RNFT1, RWDD4, SAMD9L, SART3, SCAF4, SCD, SEC22A, SEC61A1,SERPINE2, SF1, SLC25A17, SLC7A6, SLC7A8, SMN2, SMYD3, SMYD5, SNAP23,SNHG16, SQLE, SQRDL, SQSTM1, SRCAP, SREBF1, STARD4, STAT1, STAU1,STEAP2, STRN3, SYNE1, TACC1, TAF2, TANC2, TARBP1, TBC1D15, TEP1, TFCP2,TGFBRAP1, THADA, TIMP2, TLK1, TMEM154, TNS3, TOMM5, TRAF3, TRAK1,TRAPPC12, TRIM2, TRIM26, TRIM65, TSPAN2, U2SURP, UBAP2L, UBE2V1, UCHL5,UHRF1BP1L, VANGL1, VARS2, VPS13A, VP529, VWA8, WSB1, XIAP, XRN2, YPEL5,ZAK, ZC3H18, ZFAND5, ZMIZ1, ZMYM2, ZNF219, ZNF227, ZNF24, ZNF37A,ZNF37BP, ZNF395, ZNF652, ZNF674, ZNF74 or ZNF778.

Table 2 shows 234 genes that, in the presence of Compound 774 (0.3 □M),demonstrate an effect on isoform fold increase having a statisticallysignificant adjusted p value of at least 0.01.

TABLE 2 ABCC1, ACADVL, ADAM15, AGPAT3, AHRR, AJUBA, AKAP1, AKAP9, ALCAM,ALDH4A1, ANKFY1, AP2B1, APLP2, APP, ARID1A, ARID2, ASPH, ATMIN, BASP1,BC033281, BCAR3, C11orf73, C17orf76-AS1, C5orf24, C6orf48, CAB39,CASP8AP2, CAV1, CCAR1, CCT6A, CD276, CD46, CDC25B, CDK16, CEP68, CHD8,CLIC1, COL12A1, CPEB2, CREB5, CRLS1, CRTAP, CTNND1, CUX1, CYBRD1, DACT1,DCAF10, DCAF11, DDHD2, DDX39B, DIAPH3, DKK3, DLC1, DSTN, EBF1, EGR1,EIF4G1, EIF4G3, ENG, ERC1, ETV5, FAM198B, FAM219A, FAM3C, FEZ1,FGD5-AS1, FLII, FN1, FNBP1, FOS, FOSB, FOXKl, FOXM1, FYN, GABPB1, GALC,GALNT1, GBA2, GGCT, GHDC, GMIP, GNA13, GNAS, GNL3L, GOLGA2, GORASP1,GREM1, GSE1, HAUS6, HDAC7, HEG1, HLA-A, HLA-E, HMGA1, HP1BP3, IL6ST,ITGAV, KIAA1549, KIF14, KLC1, KLF6, KLHL7, KRT18, LAMA2, LAMB1, LARP7,LATS2, LGALS8, LIMS1, LINC00341, LONP1, LOX, MDM2, MEPCE, MINPP1, MLLT4,MPPE1, MRPL3, MSH2, MSH6, MSL3, MTMR9, MTRR, MUM1, MYADM, MYLK, NADK,NAV2, NCSTN, NFE2L1, NID1, NIPA1, NPEPPS, NRD1, NUDT4, NUSAP1, P4HB,PABPC1, PAK4, PAPD4, PCNXL2, PDE4A, PDXDC1, PHRF1, PHTF2, PI4K2A,PIK3C2B, PLAU, LEKHB2, PLSCR3, PLXNB2, POSTN, POU2F1, PPPARA, PPP1R12A,PRKACB, PSMD6, PTPN14, PUS7, QKI, RAB34, RAD1, RAD23B, RASSF8, RBCK1,RBFOX2, RFTN1, RNF19A, RNF38, RPS6KC1, RWDD4, SEC14L1, SEC24B, SERPINE2,SF1, SLC39A3, SLC41A1, SLC4A4, SLC7A6, SMARCA4, SMN2, SNHG16, SNX14,SON, SPRED2, STAU1, STEAP2, STRIP1, STRN3, TBL2, TGFBI, TGFBR1, THAP4,TLE3, TMEM47, TNKS1BP1, TOMM40, TOPORS, TRAK1, TRAPPC12, TRIB1, TRIM2,TRIM23, TRIM65, TRMT1L, TRPS1, TXNL1, TXNRD1, U2SURP, UBE2G2, UBE2V1,UHMK1, USP7, VPS29, VWA8, WDR19, WDR37, WIPF1, YPEL5, YTHDF3, Z24749,ZBTB10, ZBTB7A, ZFAND5, ZMIZ1, ZNF12, ZNF148, ZNF335, ZNF395, ZNF583,ZNF621, ZNF655, ZNF74 or ZNF780A.

Table 3 shows 384 genes that, in the presence of Compound 808 (3 □M),demonstrate an effect on isoform fold increase having a statisticallysignificant adjusted p value of at least 0.01.

TABLE 3 ABCB7, ABHD10, ABLIM3, ACACA, ADAM12, ADAM17, ADAM33, AGK, AGPS,AHCYL2, AHDC1, AHRR, AK021888, AK310472, AKAP1, AKAP9, AKNA, AMPD2,ANKRD17, ANKS6, ANP32A, ANXA11, ANXA6, APLP2, APP, APPL2, APTX,ARHGAP22, ARMCX3, ASAP1, ASNS, ASPH, ATG9A, ATP2C1, AURKA, AXIN1,B4GALT2, BACE1, BASP1, BEND6, BICD1, BIN1, BRD2, BRPF1, BTBD10,C11orf30, C11orf73, C17orf76-AS1, C4orf27, C6orf48, CAB39, CAPNS1,CASC3, CCDC77, CCDC88A, CD46, CDC40, CDC42BPA, CDCA7, CDH13, CDK11B,CEP68, CIZ1, CLK4, CNOT1, COG1, COL12A1, COL1A1, COL6A1, COPS7B, CSDE1,CSNK1A1, CUX1, CYB5B, CYBRD1, DAB2, DARS, DCBLD2, DCUN1D4, DDAH2, DDR1,DDX39B, DDX42, DENND1A, DENND1B, DENND5A, DGKA, DHFR, DHX9, DIAPH1,DIAPH3, DIS3L, DNM2, DOCK1, DPP8, DSEL, EEA1, EFCAB14, EIF2B3, EIF4G1,EIF4G3, ELF2, ENG, ENPP2, EPN1, EXTL2, EYA3, FAF1, FAM198B, FAM3C,FBXO10, FBXO18, FBXO31, FBXO9, FER, FEZ1, FHOD3, FLII, FN1, FNBP1,FOCAD, FOSL1, FOXM1, GABPB1, GALC, GALNT1, GCFC2, GGCT, GIGYF2, GMIP,GNAS, GNL3L, GOLGB1, GPR89A, GPSM2, GREM1, GRK6, GTF2H2B, HAT1, HAUS3,HEG1, HLA-A, HLTF, HP1BP3, HRH1, HSD17B12, HSD17B4, HTT, IARS, IDH1,IGF2BP2, ITM2C, KCNK2, KIAA1033, KIAA1143, KIAA1522, KIAA1524, KIAA1715,KIF3A, KLHL7, LAMA2, LARP4, LARP7, LATS2, LIMS1, LINC00341, LINC00657,LMAN2L, LMO7, LRCH4, LRIG1, LRRC8A, LTBR, LUC7L2, LZTS2, MADD, MAGED4B,MAN1A2, MAP4K4, MED1, MEDAG, MEF2D, MEIS2, MEMO1, MICAL2, MKLN1, MLLT4,MMS19, MPZL1, MSANTD3, MSC, MSL3, MTAP, MTERFD1, MTHFD1L, MYADM, MYLK,MYO9B, MYOF, NASP, NAV2, NCOA3, NCOA4, NELFA, NEO1, NEURL1B, NF2, NID2,NOL10, NPEPPS, NRG1, NSUN4, NT5C2, NT5E, NTNG1, NUP153, NUP35, NUP50,NUSAP1, ODF2, OS9, OSBPL6, P4HA1, P4HB, PABPC1, PAPD4, PARN, PARP4,PCBP2, PCBP4, PCDHGB3, PCGF3, PCM1, PCMTD2, PDE7A, PDXDC1, PEPD, PFKP,PHF19, PHRF1, PHTF2, PIEZO1, PIGU, PITPNA, PITPNB, PITPNM1, PLAU,PLSCR3, PLXNC1, PMS1, POU2F1, PPAPDC1A, PPHLN1, PPIP5K1, PPP1R12A,PRKDC, PRMT1, PRSS23, PSMA4, PTK2B, PUF60, PVR, RAB23, RAB2B, RAD1,RAD23B, RAP1A, RAP1GDS1, RARG, RASSF8, RBCK1, RCC1, RFWD2, RGS3, RNF14,RNFT1, RPL10, RRBP1, RWDD4, SAR1A, SCAF4, SCAF8, SCLT1, SCO1, SDCBP,SEC22A, SEPT9, SF1, SGOL2, SLC25A17, SLC4A4, SLC7A6, SMARCC2, SMC4,SMC6, SMCHD1, SMN2, SMPD4, SMYD3, SNAP23, SNHG16, SOCS2, SOS2, SPATA20,SPATS2, SPG20, SQRDL, SREBF1, SREK1, SRSF3, STAT1, STAU1, STEAP2, STRN3,STX16, SUPT20H, SYNE1, SYNE2, SYT15, SYTL2, TAF2, TARBP1, TARS, TBL2,TCF7L2, TENC1, TENM2, TEP1, TET3, TGFBR1, THADA, THRB, TJP2, TLE3,TMEM47, TMEM63A, TNFAIP3, TNIP1, TNPO3, TNS1, TNS3, TOE1, TOMM5,TP53INP1, TRAF3, TRAPPC12, TRIM2, TRIM23, TRIM65, TSC2, TSPAN2, TUBB2C,TXNRD1, UBAP2L, UBE2V1, UCHL5, U5P19, VANGL1, VIPAS39, VPS29, VPS51,VWA8, WDR48, WNT5B, WSB1, WWTR1, XRN2, YAP1, YES1, YPEL5, YTHDF3,Z24749, ZBTB24, ZC3H14, ZFAND1, ZFAND5, ZHX3, ZMIZ1, ZMYM2, ZNF219,ZNF268, ZNF395, ZNF827 or ZNF91.

Table 4 shows 219 genes that, in the presence of Compound 808 (0.3 □M),demonstrate an effect on isoform fold increase having a statisticallysignificant adjusted p value of at least 0.01.

TABLE 4 ACACA, ACADVL, AFF2, AHCYL2, AHRR, AKAP1, ALDH4A1, ANKRD17,AP2B1, APLP2, ASL, ASPH, ATG9A, ATMIN, ATXN3, BAG2, BASP1, BRPF1, BSCL2,C11orf30, C11orf73, C17orf76-AS1, C6orf48, C9orf69, CAB39, CALU, CDC25B,CDC42BPA, CDKAL1, CLIC1, COL12A1, COL1A1, COL6A1, CSNK1A1, CTDSP2, CUL2,CUL4A, DAXX, DCAF10, DDAH1, DDR1, DDX39B, DENND1A, DGCR2, DKFZp434M1735,DKK3, DNM2, DST, EEF1A1, EFCAB14, EHMT2, EIF4G1, EIF4G2, EIF4G3, ENSA,EXO1, FAM111A, FAM198B, FAM65A, FBXO34, FEZ1, FGD5-AS1, FGFRL1, FLII,FN1, FOXK1, FOXM1, FUS, GALC, GALNT1, GAS7, GCFC2, GGCT, GJC1, GNA13,GNL3L, GOLGA4, GPR1, GREM1, HEG1, HLA-A, HLA-E, HLTF, HNRNPR, HNRNPUL1,IQCE, ITGB5, ITSN1, KIAA1033, KIF2A, KIF3A, KLC2, LATS2, LIMS1,LINC00341, LINC00657, LONP1, LOX, LUC7L2, MBD1, MBOAT7, MEF2D, MEIS2,MICAL2, MKL1, MKNK2, MLST8, MPPE1, MSL3, MSRB3, MTRR, MYADM, MYLK,MYO1D, NAA35, NAV1, NAV2, NCOA1, NFX1, NKX3-1, NOMO3, NRG1, NUDT4,NUPL1, NUSAP1, OSMR, P4HA1, P4HB, PAPD4, PARD3, PARN, PARP14, PARVB,PCBP2, PCBP4, PCGF3, PDLIM7, PDXDC1, PEX5, PFKP, PHRF1, PI4K2A, POLE3,POLR3D, POSTN, PPARA, PPP6R1, PPP6R2, PRNP, PXN, RAB34, RAD23B, RALB,RAP1A, RASSF8, RBCK1, RBFOX2, RGS10, RIF1, RNF14, RNF19A, SAMD9, SCAF4,SDCBP, SERPINE2, SF1, SH3RF1, SKIL, SLC25A17, SLC4A4, SMG1, SMN2,SNHG16, SREBF1, STAT3, STC2, STEAP2, STRN3, SYNE1, SYNE2, TACC1, TARS,TGFBI, TMEM47, TNC, TNFRSF12A, TNS1, TRAF3, TRIM28, TSC2, TSHZ1, TTC7A,TUBB2C, TUBB3, TXNL1, TXNRD1, UBE2G2, UBE2V1, UBQLN4, UNC5B, USP19,VARS2, VCL, VPS29, WDR37, WIPF1, WWTR1, ZC3H12C, ZCCHC11, ZEB1, ZEB2,ZFAND1, ZFAND5, ZMIZ1, ZNF28, ZNF281, ZNF655, ZNF764 or ZNF839.Methods of Preventing and/or Treating Diseases

In another aspect, provided herein are methods for preventing and/ortreating a disease associated with the aberrant expression of a productof a gene (e.g., an mRNA transcript or protein), wherein the precursorRNA transcript transcribed from the gene comprises a REMS, the methodscomprising administering to a patient in need thereof a compound ofFormula (I) or a form thereof, or a pharmaceutical compositioncomprising a compound of Formula (I) or a form thereof and apharmaceutically acceptable carrier, excipient or diluent.

In certain embodiments, the gene is any one of the genes disclosed inTables 1-4 or 6. In certain embodiments, the gene contains a nucleotidesequence encoding a non-endogenous REMS. In one embodiment, providedherein are methods for preventing and/or treating a disease associatedwith aberrant expression of a product of a gene (e.g., an mRNA, RNAtranscript or protein), by way of nonlimiting example, disclosed inTable 6, infra, the methods comprising administering to a patient inneed thereof a compound of Formula (I) or a form thereof, or apharmaceutical composition comprising a compound of Formula (I) or aform thereof and a pharmaceutically acceptable carrier, excipient ordiluent.

In another embodiment, provided herein are methods for preventing and/ortreating a disease associated with aberrant expression of a product of agene (e.g., an mRNA, RNA transcript or protein), not disclosed in Tables1-4, infra, wherein the precursor RNA transcript transcribed from thegene comprises a REMS, the methods comprising administering to a patientin need thereof a compound of Formula (I) or a form thereof, or apharmaceutical composition comprising a compound of Formula (I) or aform thereof and a pharmaceutically acceptable carrier, excipient ordiluent.

In another embodiment, provided herein are methods for preventing and/ortreating a disease associated with aberrant expression of a product of agene (e.g., an mRNA, RNA transcript or protein), by way of nonlimitingexample, not disclosed in International Patent Application No.PCT/US2014/071252 (International Publication No. WO 2015/105657 A1),wherein the precursor RNA transcript transcribed from the gene comprisesa REMS, the methods comprising administering to a patient in needthereof a compound of Formula (I) or a form thereof, or a pharmaceuticalcomposition comprising a compound of Formula (I) or a form thereof and apharmaceutically acceptable carrier, excipient or diluent.

In another embodiment, provided herein are methods for preventing and/ortreating a disease associated with aberrant expression of a product of agene (e.g., an mRNA, RNA transcript or protein), not disclosed in Table6, infra, wherein the precursor RNA transcript transcribed from the genecomprises a REMS, the methods comprising administering to a patient inneed thereof a compound of Formula (I) or a form thereof, or apharmaceutical composition comprising a compound of Formula (I) or aform thereof and a pharmaceutically acceptable carrier, excipient ordiluent.

In another embodiment, provided herein are methods for preventing and/ortreating a disease associated with aberrant expression of a product ofERGIC3 (e.g., an mRNA, RNA transcript or protein), comprisingadministering to a patient in need thereof a compound of Formula (I) ora form thereof, or a pharmaceutical composition comprising a compound ofFormula (I) or a form thereof and a pharmaceutically acceptable carrier,excipient or diluent. See the example section for additional informationregarding the genes in Table 6.

In another aspect, provided herein are methods for preventing and/ortreating a disease in which a change in the level of expression of one,two, three or more RNA isoforms encoded by a gene is beneficial to theprevention and/or treatment of the disease, wherein the precursor RNAtranscript transcribed from the gene comprises a REMS, the methodscomprising administering to a patient in need thereof a compound ofFormula (I) or a form thereof, or a pharmaceutical compositioncomprising a compound of Formula (I) or a form thereof and apharmaceutically acceptable carrier, excipient or diluent.

In certain embodiments, the gene is any one of the genes disclosed inTables 1-4 or 6. In certain embodiments, the gene contains a nucleotidesequence encoding the non-endogenous REMS. In one embodiment, providedherein are methods for preventing and/or treating a disease in which thealteration (e.g., increase or decrease) in the expression one, two,three or more RNA isoforms encoded by a gene, by way of nonlimitingexample, disclosed in Table 6, infra, is beneficial to the preventionand/or treatment of the disease, the methods comprising administering toa patient in need thereof a compound of Formula (I) or a form thereof,or a pharmaceutical composition comprising a compound of Formula (I) ora form thereof and a pharmaceutically acceptable carrier, excipient ordiluent. In another embodiment, provided herein are methods forpreventing and/or treating a disease in which the alteration (e.g.,increase or decrease) in the expression one, two, three or more RNAisoforms encoded by a gene, not disclosed in Tables 1-4, infra, isbeneficial to the prevention and/or treatment of the disease, whereinthe precursor RNA transcript transcribed from the gene comprises a REMS,the methods comprising administering to a patient in need thereof acompound of Formula (I) or a form thereof, or a pharmaceuticalcomposition comprising a compound of Formula (I) or a form thereof and apharmaceutically acceptable carrier, excipient or diluent. In anotherembodiment, provided herein are methods for preventing and/or treating adisease in which the alteration (e.g., increase or decrease) in theexpression one, two, three or more RNA isoforms encoded by a gene, notdisclosed in International Patent Application No. PCT/US2014/071252(International Publication No. WO 2015/105657 A1), is beneficial to theprevention and/or treatment of the disease, wherein the precursor RNAtranscript transcribed from the gene comprises a REMS, the methodscomprising administering to a patient in need thereof a compound ofFormula (I) or a form thereof, or a pharmaceutical compositioncomprising a compound of Formula (I) or a form thereof and apharmaceutically acceptable carrier, excipient or diluent. In anotherembodiment, provided herein are methods for preventing and/or treating adisease in which the alteration (e.g., increase or decrease) in theexpression one, two, three or more RNA isoforms encoded by a gene, notdisclosed in Table 6, infra, is beneficial to the prevention and/ortreatment of the disease, wherein the precursor RNA transcripttranscribed from the gene comprises a REMS, the methods comprisingadministering to a patient in need thereof a compound of Formula (I) ora form thereof, or a pharmaceutical composition comprising a compound ofFormula (I) or a form thereof and a pharmaceutically acceptable carrier,excipient or diluent. In another embodiment, provided herein are methodsfor preventing and/or treating a disease in which the alteration (e.g.,increase or decrease) in the expression one, two, three or more RNAisoforms encoded by ERGIC3, is beneficial to the prevention and/ortreatment of the disease, the methods comprising administering to apatient in need thereof a compound of Formula (I) or a form thereof, ora pharmaceutical composition comprising a compound of Formula (I) or aform thereof and a pharmaceutically acceptable carrier, excipient ordiluent. In a specific embodiment, one, two, three or more RNA isoformsencoded by ERGIC3 are decreased following administration of a compoundof Formula (I) or a form thereof and a pharmaceutically acceptablecarrier, excipient or diluent. See the example section for additionalinformation regarding the genes in Table 6.

In another aspect, provided herein are methods for preventing and/ortreating a disease in which a change in the level of expression of one,two, three or more protein isoforms encoded by a gene is beneficial tothe prevention and/or treatment of the disease, wherein the precursorRNA transcript transcribed from the gene comprises a REMS, the methodscomprising administering to a patient in need thereof a compound ofFormula (I) or a form thereof, or a pharmaceutical compositioncomprising a compound of Formula (I) or a form thereof and apharmaceutically acceptable carrier, excipient or diluent.

In certain embodiments, the gene is any one of the genes disclosed inTables 1-4 or 6. In certain embodiments, the gene contains a nucleotidesequence encoding a non-endogenous REMS. In one embodiment, providedherein are methods for preventing and/or treating a disease in which thealteration (e.g., increase or decrease) in the expression one, two,three or more protein isoforms encoded by a gene, by way of nonlimitingexample, disclosed in Table 6, infra, is beneficial to the preventionand/or treatment of the disease, the methods comprising administering toa patient in need thereof a compound of Formula (I) or a form thereof,or a pharmaceutical composition comprising a compound of Formula (I) ora form thereof and a pharmaceutically acceptable carrier, excipient ordiluent.

In another embodiment, provided herein are methods for preventing and/ortreating a disease in which the alteration (e.g., increase or decrease)in the expression one, two, three or more protein isoforms encoded by agene, not disclosed in Tables 1-4, infra, is beneficial to theprevention and/or treatment of the disease, wherein the precursor RNAtranscript transcribed from the gene comprises a REMS, the methodscomprising administering to a patient in need thereof a compound ofFormula (I) or a form thereof, or a pharmaceutical compositioncomprising a compound of Formula (I) or a form thereof and apharmaceutically acceptable carrier, excipient or diluent.

In another embodiment, provided herein are methods for preventing and/ortreating a disease in which the alteration (e.g., increase or decrease)in the expression one, two, three or more protein isoforms encoded by agene, not disclosed in International Patent Application No.PCT/US2014/071252 (International Publication No. WO 2015/105657 A1), isbeneficial to the prevention and/or treatment of the disease, whereinthe precursor RNA transcript transcribed from the gene comprises a REMS,the methods comprising administering to a patient in need thereof acompound of Formula (I) or a form thereof, or a pharmaceuticalcomposition comprising a compound of Formula (I) or a form thereof and apharmaceutically acceptable carrier, excipient or diluent.

In another embodiment, provided herein are methods for preventing and/ortreating a disease in which the alteration (e.g., increase or decrease)in the expression one, two, three or more protein isoforms encoded by agene, not disclosed in Table 6, infra, is beneficial to the preventionand/or treatment of the disease, wherein the precursor RNA transcripttranscribed from the gene comprises a REMS, the methods comprisingadministering to a patient in need thereof a compound of Formula (I) ora form thereof, or a pharmaceutical composition comprising a compound ofFormula (I) or a form thereof and a pharmaceutically acceptable carrier,excipient or diluent.

In another embodiment, provided herein are methods for preventing and/ortreating a disease in which the alteration (e.g., increase or decrease)in the expression one, two, three or more protein isoforms encoded byERGIC3, is beneficial to the prevention and/or treatment of the disease,the methods comprising administering to a patient in need thereof acompound of Formula (I) or a form thereof, or a pharmaceuticalcomposition comprising a compound of Formula (I) or a form thereof and apharmaceutically acceptable carrier, excipient or diluent. In a specificembodiment, one, two, three or more RNA isoforms encoded by ERGIC3 aredecreased following administration of a compound of Formula (I) or aform thereof and a pharmaceutically acceptable carrier, excipient ordiluent. See the example section for additional information regardingthe genes in Table 6.

In some embodiments, the compound of Formula (I) or a form thereof thatis administered to a subject is a compound of Formula (II), Formula(III), Formula (IV), Formula (V), Formula (VI), Formula (VII), Formula(VIII), Formula (IX), Formula (X), Formula (XI), Formula (XII), Formula(XIII), or Formula (XIV). In some embodiments, the compound of Formula(I) or a form thereof that is administered to a subject is a compounddescribed herein.

In a specific embodiment, the methods for preventing a disease describedherein prevent the onset or development of one or symptoms of thedisease. In another embodiment, the methods for preventing a diseasedescribed herein prevent the recurrence of the disease or delays therecurrence of the disease. In another embodiment, the methods fortreating a disease described herein has one, two or more of the effects:(i) reduce or ameliorate the severity of the disease; (ii) inhibit theprogression of the disease; (iii) reduce hospitalization of a subject;(iv) reduce hospitalization length for a subject; (v) increase thesurvival of a subject; (vi) improve the quality of life of a subject;(vii) reduce the number of symptoms associated with the disease; (viii)reduce or ameliorates the severity of a symptom(s) associated with thedisease; (ix) reduce the duration of a symptom(s) associated with thedisease; (x) prevent the recurrence of a symptom associated with thedisease; (xi) inhibit the development or onset of a symptom of thedisease; and/or (xii) inhibit of the progression of a symptom associatedwith the disease.

In certain embodiments, the disease or disorder prevented and/or treatedin accordance with a method described herein is a disease or disorderassociated with a gene listed in Table 6. In specific embodiments, thedisease or disorder prevented and/or treated in accordance with a methoddescribed herein is leukemia, acute myeloid leukemia, colon cancer,gastric cancer, macular degeneration, acute monocytic leukemia, breastcancer, combined methylmalonic aciduria and homocystinuria, cblC type,hepatocellular carcinoma, cone-rod dystrophy, alveolar soft partsarcoma, myeloma, skin melanoma, prostatitis, pancreatitis, pancreaticcancer, retinitis, adenocarcinoma, adenoiditis, adenoid cysticcarcinoma, cataract, retinal degeneration, gastrointestinal stromaltumor, Wegener's granulomatosis, sarcoma, myopathy, prostateadenocarcinoma, Alzheimer's disease, hyperprolinemia, acne,tuberculosis, succinic semialdehyde dehydrogenase deficiency,esophagitis, mental retardation, esophageal adenocarcinoma, glycineencephalopathy, Crohn's disease, spina bifida, tuberculosis, autosomalrecessive disease, schizophrenia, neural tube defects, lung cancer,myelodysplastic syndromes, amyotropic lateral sclerosis, neuronitis,germ cell tumors, Parkinson's disease, talipes equinovarus,dystrophinopathies, Hodgkin's lymphoma, ovarian cancer, non-Hodgkin'slymphoma, multiple myeloma, chronic myeloid leukemia, ischemia, acutelymphoblastic leukemia, renal cell carcinoma, transitional cellcarcinoma, colorectal cancer, chronic lymphocytic leukemia, anaplasticlarge cell lymphoma, kidney cancer, cerebritis, bladder relateddisorders, breast cancer, cervical cancer, cleft lip, cleft palate,cervicitis, spasticity, lipoma, scleroderma, Gitelman syndrome,poliomyelitis, paralysis, Aagenaes syndrome, or oculomotor nerveparalysis. In specific embodiments, the disease or disorder preventedand/or treated in accordance with a method described herein is basalcell carcinoma, goblet cell metaplasia, or a malignant glioma. In otherspecific embodiments, the disease or disorder prevented and/or treatedin accordance with a method described herein is a cancer of the liver,breast, lung, prostate, cervix, uterus, colon, pancreas, kidney,stomach, bladder, ovary, or brain.

In certain embodiments, the disease prevented and/or treated inaccordance with a method described herein is cancer amenable totreatment by upregulation or downregulation of a gene or isoform thereofas described herein. In specific embodiments, cancers that can beprevented and/or treated in accordance with a method described hereininclude, but are not limited to, cancer of the head, neck, eye, mouth,throat, esophagus, esophagus, chest, bone, lung, kidney, colon, rectumor other gastrointestinal tract organs, stomach, spleen, skeletalmuscle, subcutaneous tissue, prostate, breast, ovaries, testicles orother reproductive organs, skin, thyroid, blood, lymph nodes, kidney,liver, pancreas, brain or central nervous system.

Specific examples of cancers that can be prevented and/or treated inaccordance with the methods provided herein include, but are not limitedto, the following: renal cancer, kidney cancer, glioblastoma multiforme,metastatic breast cancer; breast carcinoma; breast sarcoma;neurofibroma; neurofibromatosis; pediatric tumors; neuroblastoma;malignant melanoma; carcinomas of the epidermis; leukemias such as butnot limited to, acute leukemia, acute lymphocytic leukemia, acutemyelocytic leukemias such as myeloblastic, promyelocytic,myelomonocytic, monocytic, erythroleukemia leukemias and myclodysplasticsyndrome, chronic leukemias such as but not limited to, chronicmyclocytic (granulocytic) leukemia, chronic lymphocytic leukemia, hairycell leukemia; polycythemia vera; lymphomas such as but not limited toHodgkin's disease, non-Hodgkin's disease; multiple myelomas such as butnot limited to smoldering multiple mycloma, nonsecretory myeloma,osteosclerotic myeloma, plasma cell leukemia, solitary plasmacytoma andextramedullary plasmacytoma; Waldenstrom's macroglobulinemia; monoclonalgammopathy of undetermined significance; benign monoclonal gammopathy;heavy chain disease; bone cancer and connective tissue sarcomas such asbut not limited to bone sarcoma, myeloma bone disease, multiple myeloma,cholesteatoma-induced bone osteosarcoma, Paget's disease of bone,osteosarcoma, chondrosarcoma, Ewing's sarcoma, malignant giant celltumor, fibrosarcoma of bone, chordoma, periosteal sarcoma, soft-tissuesarcomas, angiosarcoma (hemangiosarcoma), fibrosarcoma, Kaposi'ssarcoma, leiomyosarcoma, liposarcoma, lymphangiosarcoma, neurilemmoma,rhabdomyosarcoma, and synovial sarcoma; brain tumors such as but notlimited to, glioma, astrocytoma, brain stem glioma, ependymoma,oligodendroglioma, nonglial tumor, acoustic neurinoma,craniopharyngioma, medulloblastoma, meningioma, pineocytoma,pineoblastoma, and primary brain lymphoma; breast cancer including butnot limited to adenocarcinoma, lobular (small cell) carcinoma,intraductal carcinoma, medullary breast cancer, mucinous breast cancer,tubular breast cancer, papillary breast cancer, Paget's disease(including juvenile Paget's disease) and inflammatory breast cancer;adrenal cancer such as but not limited to pheochromocytom andadrenocortical carcinoma; thyroid cancer such as but not limited topapillary or follicular thyroid cancer, medullary thyroid cancer andanaplastic thyroid cancer; pancreatic cancer such as but not limited to,insulinoma, gastrinoma, glucagonoma, vipoma, somatostatin-secretingtumor, and carcinoid or islet cell tumor; pituitary cancers such as butlimited to Cushing's disease, prolactin-secreting tumor, acromegaly, anddiabetes insipius; eye cancers such as but not limited to ocularmelanoma such as iris melanoma, choroidal melanoma, and cilliary bodymelanoma, and retinoblastoma; vaginal cancers such as squamous cellcarcinoma, adenocarcinoma, and melanoma; vulvar cancer such as squamouscell carcinoma, melanoma, adenocarcinoma, basal cell carcinoma, sarcoma,and Paget's disease; cervical cancers such as but not limited to,squamous cell carcinoma, and adenocarcinoma; uterine cancers such as butnot limited to endometrial carcinoma and uterine sarcoma; ovariancancers such as but not limited to, ovarian epithelial carcinoma,borderline tumor, germ cell tumor, and stromal tumor; cervicalcarcinoma; esophageal cancers such as but not limited to, squamouscancer, adenocarcinoma, adenoid cyctic carcinoma, mucoepidermoidcarcinoma, adenosquamous carcinoma, sarcoma, melanoma, plasmacytoma,verrucous carcinoma, and oat cell (small cell) carcinoma; stomachcancers such as but not limited to, adenocarcinoma, fungating(polypoid), ulcerating, superficial spreading, diffusely spreading,malignant lymphoma, liposarcoma, fibrosarcoma, and carcinosarcoma; coloncancers; KRAS-mutated colorectal cancer; colon carcinoma; rectalcancers; liver cancers such as but not limited to hepatocellularcarcinoma and hepatoblastoma, gallbladder cancers such asadenocarcinoma; cholangiocarcinomas such as but not limited topapillary, nodular, and diffuse; lung cancers such as KRAS-mutatednon-small cell lung cancer, non-small cell lung cancer, squamous cellcarcinoma (epidermoid carcinoma), adenocarcinoma, large-cell carcinomaand small-cell lung cancer; lung carcinoma; testicular cancers such asbut not limited to germinal tumor, seminoma, anaplastic, classic(typical), spermatocytic, nonseminoma, embryonal carcinoma, teratomacarcinoma, choriocarcinoma (yolk-sac tumor), prostate cancers such asbut not limited to, androgen-independent prostate cancer,androgen-dependent prostate cancer, adenocarcinoma, leiomyosarcoma, andrhabdomyosarcoma; penal cancers; oral cancers such as but not limited tosquamous cell carcinoma; basal cancers; salivary gland cancers such asbut not limited to adenocarcinoma, mucoepidermoid carcinoma, andadenoidcystic carcinoma; pharynx cancers such as but not limited tosquamous cell cancer, and verrucous; skin cancers such as but notlimited to, basal cell carcinoma, squamous cell carcinoma and melanoma,superficial spreading melanoma, nodular melanoma, lentigo malignantmelanoma, acral lentiginous melanoma; kidney cancers such as but notlimited to renal cell cancer, adenocarcinoma, hypernephroma,fibrosarcoma, transitional cell cancer (renal pelvis and/or uterer);renal carcinoma; Wilms' tumor; bladder cancers such as but not limitedto transitional cell carcinoma, squamous cell cancer, adenocarcinoma,carcinosarcoma. In addition, cancers include myxosarcoma, osteogenicsarcoma, endotheliosarcoma, lymphangioendotheliosarcoma, mesothelioma,synovioma, hemangioblastoma, epithelial carcinoma, cystadenocarcinoma,bronchogenic carcinoma, sweat gland carcinoma, sebaceous glandcarcinoma, papillary carcinoma and papillary adenocarcinomas.

In certain embodiments cancers that can be prevented and/or treated inaccordance with the methods provided herein include, the following:pediatric solid tumor, Ewing's sarcoma, Wilms tumor, neuroblastoma,neurofibroma, carcinoma of the epidermis, malignant melanoma, cervicalcarcinoma, colon carcinoma, lung carcinoma, renal carcinoma, breastcarcinoma, breast sarcoma, metastatic breast cancer, HIV-relatedKaposi's sarcoma, prostate cancer, androgen-independent prostate cancer,androgen-dependent prostate cancer, neurofibromatosis, lung cancer,non-small cell lung cancer, KRAS-mutated non-small cell lung cancer,malignant melanoma, melanoma, colon cancer, KRAS-mutated colorectalcancer, glioblastoma multiforme, renal cancer, kidney cancer, bladdercancer, ovarian cancer, hepatocellular carcinoma, thyroid carcinoma,rhabdomyosarcoma, acute myeloid leukemia, and multiple myeloma.

In certain embodiments, cancers and conditions associated therewith thatare prevented and/or treated in accordance with the methods providedherein are breast carcinomas, lung carcinomas, gastric carcinomas,esophageal carcinomas, colorectal carcinomas, liver carcinomas, ovariancarcinomas, thecomas, arrhenoblastomas, cervical carcinomas, endometrialcarcinoma, endometrial hyperplasia, endometriosis, fibrosarcomas,choriocarcinoma, head and neck cancer, nasopharyngeal carcinoma,laryngeal carcinomas, hepatoblastoma, Kaposi's sarcoma, melanoma, skincarcinomas, hemangioma, cavernous hemangioma, hemangioblastoma, pancreascarcinomas, retinoblastoma, astrocytoma, glioblastoma, Schwannoma,oligodendroglioma, medulloblastoma, neuroblastomas, rhabdomyosarcoma,osteogenic sarcoma, leiomyosarcomas, urinary tract carcinomas, thyroidcarcinomas, Wilm's tumor, renal cell carcinoma, prostate carcinoma,abnormal vascular proliferation associated with phakomatoses, edema(such as that associated with brain tumors), or Meigs' syndrome. Inspecific embodiment, the cancer astrocytoma, an oligodendroglioma, amixture of oligodendroglioma and an astrocytoma elements, an ependymoma,a meningioma, a pituitary adenoma, a primitive neuroectodermal tumor, amedullblastoma, a primary central nervous system (CNS) lymphoma, or aCNS germ cell tumor. In specific embodiments, the cancer treated inaccordance with the methods provided herein is an acoustic neuroma, ananaplastic astrocytoma, a glioblastoma multiforme, or a meningioma. Inother specific embodiments, the cancer treated in accordance with themethods provided herein is a brain stem glioma, a craniopharyngioma, anependyoma, a juvenile pilocytic astrocytoma, a medulloblastoma, an opticnerve glioma, primitive neuroectodermal tumor, or a rhabdoid tumor.

Specific examples of conditions that can be prevented and/or treated inaccordance with the methods described herein include cystic fibrosis,muscular dystrophy, polycystic autosomal-dominant kidney disease,cancer-induced cachexia, benign prostatic hyperplasia, rheumatoidarthritis, psoriasis, atherosclerosis, obesity, retinopathies (includingdiabetic retinopathy and retinopathy of prematurity), retrolentalfibroplasia, neovascular glaucoma, age-related macular degeneration,exudative macular degeneration, thyroid hyperplasias (including Grave'sdisease), corneal and other tissue transplantation, epidemickeratoconjunctivitis, Vitamin A deficiency, contact lens overwear,atopic keratitis, superior limbic keratitis, and pterygium keratitissicca, viral infections, inflammation associated with viral infections,chronic inflammation, lung inflammation, nephrotic syndrome,preeclampsia, ascites, pericardial effusion (such as that associatedwith pericarditis), pleural effusion, Sjogren's syndrome, acne rosacea,phylectenulosis, syphilis, lipid degeneration, chemical burns, bacterialulcers, fungal ulcers, Herpes simplex infection, Herpes zosterinfections, protozoan infections, Mooren's ulcer, Terrien's marginaldegeneration, marginal keratolysis, systemic lupus, polyarteritis,trauma, Wegener's sarcoidosis, Paget's disease, scleritis,Stevens-Johnson's disease, pemphigoid, radial keratotomy, Eales'disease, Behcet's disease, sickle cell anemia, pseudoxanthoma elasticum,Stargardt's disease, pars planitis, chronic retinal detachment, veinocclusion, artery occlusion, carotid obstructive disease, chronicuveitis/vitritis, ocular histoplasmosis, Mycobacteria infections, Lyme'sdisease, Best's disease, myopia, optic pits, hyperviscosity syndromes,toxoplasmosis, sarcoidosis, trauma, post-laser complications, diseasesassociated with rubeosis (neovascularization of the iris and of theangle), and diseases caused by the abnormal proliferation offibrovascular or fibrous tissue, including all forms of prolificvitreoretinopathy. Certain examples of non-neoplastic conditions thatcan be prevented and/or treated in accordance with the methods describedherein include viral infections, including but not limited to, thoseassociated with viruses belonging to Flaviviridae, flavivirus,pestivirus, hepacivirus, West Nile virus, hepatitis C virus (HCV) orhuman papilloma virus (HPV).

Artificial Gene Constructs

In one aspect, provided herein are artificial gene constructs comprisinga REMS. In one embodiment, an artificial gene construct comprisesgenomic DNA or DNA encoding exons and one, two or more introns, whereina nucleotide sequence encoding a 5′ splice site, which is upstream of anucleotide sequence a branch point and a nucleotide sequence encoding a3′ splice site, is modified to introduce a nucleotide sequence encodinga REMS. In another embodiment, an artificial gene construct comprisesDNA encoding exons, a 5′ splice site(s), a 3′ splice site(s) and abranch point(s), wherein a nucleotide sequence encoding a 5′ splicesite, which is upstream of at least one nucleotide sequence encoding abranch point and at least one nucleotide sequence encoding a 3′ splicesite, is modified to introduce a nucleotide sequence encoding a REMS. Inanother embodiment, an artificial gene construct comprises DNA encodingexons, a 3′ splice site(s) and a branch point(s), wherein a nucleotidesequence encoding an exon, which is upstream of a nucleotide sequenceencoding a branch point and a 3′ splice site, is modified to introduce anucleotide sequence encoding a REMS. In some embodiments, an artificialgene construct comprises a DNA sequence that is modified to introduce anucleotide sequence encoding a REMS, wherein the location of the REMS isas illustrated in any of FIGS. 1A-1D. In certain embodiments, the DNAsequence chosen to be used in the production of an artificial geneconstruct contains a nucleotide sequence encoding a REMS and anadditional nucleotide sequence encoding a REMS is introduced. Inspecific embodiments, the nucleotide sequence encoding a REMS is anucleotide sequence encoding a non-endogenous REMS, i.e., not naturallyfound in the DNA sequence of the artificial gene construct. In certainembodiments, the artificial gene construct comprises other elements,such as a promoter (e.g., a constitutive, inducible or tissue specificpromoter), a Poly(A) site, a transcription termination site, and atranscription binding site(s). In certain embodiments, the artificialgene construct comprises at least the exons of a gene encoding atherapeutic protein. In some embodiments, the artificial gene constructcomprises at least the exons of a gene listed in Table 1, 2, 3, 4 or 6.In certain embodiments, the artificial gene construct comprises at leastthe exons of one of the following genes: SMN2, RIG-I, MDA5, LGP2, TLR7,TLR9, interferon gamma, vascular endothelial growth factor (VEGF), HER2,PSK9, Insulin receptor, CHM, growth hormone, IGF1, utrophin (UTRN), orEPO. In other embodiments, the artificial gene construct comprises atleast the exons of a detectable reporter gene, such as green fluorescentprotein (GFP), yellow fluorescent protein (YFP), red fluorescentprotein, beta galactosidase, renilla luciferase, firefly luciferase,etc.

In certain embodiments, an artificial gene construct is produced asfollows: a nucleotide sequence encoding a REMS is introduced into anucleotide sequence encoding an existing 5′ splice site of genomic DNAor DNA, wherein the DNA encodes two or more exons and one or moreintrons, and wherein the nucleotide sequence encoding the existing 5′splice site is upstream of a nucleotide sequence encoding a 3′ splicesite. In some embodiments, an artificial gene construct is produced asfollows: a nucleotide sequence encoding a REMS is introduced upstream ofa nucleotide sequence encoding a branch point and a 3′ splice site ofgenomic DNA or DNA, wherein the DNA encodes two or more exons and anintron(s). In a specific embodiment, the nucleotide sequence encodingthe REMS is introduced internally within a nucleotide sequence encodingan exon. In certain embodiments, an artificial gene construct isproduced as follows: a nucleotide sequence encoding a REMS, a nucleotidesequence encoding a branch point, and a nucleotide sequence encoding a3′ splice site are introduced into a cDNA, wherein the nucleotidesequence encoding the REMS is upstream of the branch point and 3′ splicesite. The nucleotide sequence encoding the REMS can function as a 5′splice site. In certain embodiments, the nucleotide sequence encodingthe REMS is internally within an exon. In a specific embodiment, thegenomic DNA or DNA chosen for use in the production of an artificialgene construct does not contain a nucleotide sequence encoding a REMS.In certain embodiments, the genomic DNA or DNA chosen for use in theproduction of an artificial gene construct contains a REMS and anadditional REMS is introduced. In introducing a nucleotide sequenceencoding a REMS into a DNA sequence, care should be taken so as not todisrupt an open reading frame or introduce a stop codon. Theintroduction of a nucleotide sequence encoding a REMS into a DNAsequence may or may not result in an amino acid change at the proteinlevel. In certain embodiments, the introduction of a nucleotide sequenceencoding a REMS into a DNA sequence results in an amino acid change atthe protein level. In some embodiments, this amino acid change is aconservative amino acid substitution. In other embodiments, theintroduction of a nucleotide sequence encoding a REMS into a DNAsequence does not result in an amino acid change at the protein level.Techniques known to one of skill in the art may be used to introduce aREMS and other elements, such as a branch point or 3′ splice site into aDNA sequence, e.g., gene editing techniques such as the CRISPR-Casapproach, Transcription Activator-Like Effector Nucleases (TALENs), orZinc finger nucleases (ZFNs) may be used.

In certain embodiments, an artificial gene construct comprises an RNAsequence comprising exons and one, two or more introns, wherein a 5′splice site, which is upstream of a 3′ splice site, is modified tointroduce a REMS. In another embodiment, an artificial gene constructcomprises an RNA sequence comprising exons, a 5′ splice site(s), a 3′splice site(s) and a branch point(s), wherein a 5′ splice site, which isupstream of a 3′ splice site, is modified to introduce a REMS. Inanother embodiment, an artificial gene construct comprises an RNAsequence comprising exons, a 3′ splice site(s) and a branch point(s),wherein an exon, which is upstream of a 3′ splice site, is modified tointroduce a REMS. In specific embodiments, the REMS is non-endogenous,i.e., not naturally found in the RNA sequence of the artificial geneconstruct. In certain embodiments, the artificial gene constructcomprises other elements, such as a promoter (e.g., a tissue-specificpromoter or constitutively expressed promoter), 5′ untranslated region,3′ untranslated region, a binding site(s) for RNA binding proteins, asmall molecule RNA sensor(s), e.g., riboswitches, stem-loop structures,and/or internal ribosome entry sites (IRES), etc. In certainembodiments, the artificial gene construct comprises at least the exonsof a gene encoding a therapeutic protein. In some embodiments, theartificial gene construct comprises at least the exons of a gene listedin Table 1, 2, 3, 4 or 6. In certain embodiments, the artificial geneconstruct comprises at least the exons of one of the following genes:SMN2, RIG-I, MDA5, LGP2, TLR7, TLR9, interferon gamma, vascularendothelial growth factor (VEGF), HER2, PSK9, Insulin receptor, CHM,growth hormone, IGF1, utrophin (UTRN), or EPO. In a specific embodiment,the RNA transcript chosen to be used in the production of an artificialgene construct does not contain a REMS. In certain embodiments, the RNAtranscript chosen to use in the production of an artificial geneconstruct contains a REMS and an additional REMS is introduced. In otherembodiments, the artificial gene construct comprises at least the exonsof a detectable reporter gene, such as green fluorescent protein (GFP),yellow fluorescent protein (YFP), red fluorescent protein, betagalactosidase, renilla luciferase, firefly luciferase, etc.

In certain embodiments, an artificial gene construct is produced asfollows: a REMS is introduced into an existing 5′ splice site ofprecursor RNA, wherein the RNA comprises two or more exons and one ormore introns, and wherein the existing 5′ splice site is upstream of a3′ splice site. In some embodiments, an artificial gene construct isproduced as follows: a REMS is introduced upstream of a 3′ splice siteof precursor RNA, wherein the RNA comprises two or more exons and anintron(s). In a specific embodiment, the REMS is introduced internallywithin an exon. In certain embodiments, an artificial gene construct isproduced as follows: a REMS, branch point, and a 3′ splice site areintroduced into an mRNA, wherein the REMS is upstream of the branchpoint and 3′ splice site. The REMS can be a 5′ splice site. In certainembodiments, the REMS is internally with an exon. In introducing a REMSinto an RNA sequence, care should be taken so as not to disrupt an openreading frame or introduce a stop codon. The introduction of a REMS intoan RNA transcript may or may not result in an amino acid change at theprotein level. In certain embodiments, the introduction of a REMS intoan RNA transcript results in an amino acid change at the protein level.In some embodiments, this amino acid change is a conservative amino acidsubstitution. In other embodiments, the introduction of a REMS into anRNA transcript does not result in an amino acid change at the proteinlevel. Techniques known to one of skill in the art may be used tointroduce a REMS and other elements, such as a branch point or 3′ splicesite into an RNA transcript.

In some embodiments, an artificial gene construct is present in a viralvector (e.g., an adeno-associated virus (AAV), self-complimentaryadeno-associated virus, adenovirus, retrovirus, lentivirus (e.g., Simianimmunodeficiency virus, human immunodeficiency virus, or modified humanimmunodeficiency virus), Newcastle disease virus (NDV), herpes virus(e.g., herpes simplex virus), alphavirus, vaccinia virus, etc.), aplasmid, or other vector (e.g., non-viral vectors, such as lipoplexes,liposomes, polymerosomes, or nanoparticles).

In some embodiments the artificial gene construct is an RNA moleculemodified to enable cellular uptake. In certain embodiments, theartificial gene construct is an RNA molecule containing pseudouridine orother modified/artificial nucleotides for enhanced cellular uptake andgene expression.

The use of an artificial gene construct described herein in gene therapyallows one to regulate the amount of a functional protein produced fromthe construct depending on whether or not a compound described herein ispresent. The compound is essentially a tunable switch that, depending onthe amount and duration of the dose of the compound, regulates theamount of functional protein produced.

In certain embodiments, an RNA transcript transcribed from an artificialgene construct that is DNA would not produce or produce substantiallyless functional protein in the absence of a compound described hereinthan the amount of functional protein produced in the presence of acompound described herein. For example, if the artificial gene constructcomprises a nucleotide sequence encoding a REMS in a 5′ splice site,which is upstream of a nucleotide sequence encoding a 3′ splice site,then less splicing would occur in the absence of the compound and thiswould result in exon skipping which would ultimately result in lessfunctional protein being produced. In a particular example, if there isan IGF1 precursor mRNA containing a REMS-controlled exon, then in theabsence of a compound described herein an exon-skipped mRNA is producedwhich cannot be translated into full length, functional IGF1. However,in the presence of a compound described herein, a full length,functional IGF1 protein is produced. Alternatively, in certainembodiments, an RNA transcript transcribed from an artificial geneconstruct that is DNA would not produce or would produce substantiallyless functional protein in the presence of a compound described hereinthan the amount of functional protein produced in the absence of acompound described herein. For example, if the artificial gene constructcomprises a nucleotide sequence encoding a REMS in the middle of anexon, then ectopic splicing would occur in the presence of a compounddescribed herein and this would result in reduction in the production ofthe functional protein. However, in the absence of a compound describedherein, the normal splicing would occur, and the production of thefunctional protein will not be reduced. Either way, the amount of thefunctional protein produced can be titrated based on amount of acompound used and duration of exposure to the compound.

In certain embodiments, an artificial gene construct or vectorcomprising an artificial gene construct is used in cell culture. Forexample, in a cell(s) transfected with an artificial gene construct ortransduced with a vector comprising an artificial gene construct, theamount of a functional protein produced from the artificial geneconstruct can be altered depending upon whether or not a compounddescribed herein is contacted with the transfected cell(s). For example,if the artificial gene construct comprises a nucleotide sequenceencoding a REMS in a 5′ splice site, which is upstream of a nucleotidesequence encoding a 3′ splice site, then less splicing would occur inthe absence of the compound and this would result in exon skipping whichwould ultimately result in less functional protein being produced. Thus,the use of an artificial gene construct described herein allows one toregulate the amount of a functional protein produced from the constructdepending on whether or not a compound described herein is present. Inother words, a compound described herein is essentially a switch thatregulates the amount of functional protein produced. This regulation ofthe production of functional protein could be useful, e.g., when tryingto assess the role of certain genes or the effects of certain agents onpathways. The amount of the functional protein produced can be modifiedbased on the amount of a compound described herein that is contactedwith the transfected cell and/or how long the compound is contacted withthe transfected cell.

In certain embodiments, an animal (e.g., a non-human animal, such as amouse, rat, fly, etc.) is engineered to contain an artificial geneconstruct or a vector comprising an artificial gene construct.Techniques known to one of skill in the art may be used to engineer suchanimals. The amount of functional protein produced by this engineeredanimal can be regulated by whether or not a compound described herein isadministered to the animal. The amount of the functional proteinproduced can be titrated based on the dose and/or the duration ofadministration of a compound described herein to the engineered animal.In certain embodiments, the artificial gene construct encodes adetectable reporter gene, such as green fluorescent protein (GFP),yellow fluorescent protein (YFP), red fluorescent protein, betagalactosidase, renilla luciferase, firefly luciferase, etc. Inaccordance with this embodiment, the engineered animal may be used tomonitor development at different stages, visualize tissue function, etc.In other embodiments, the artificial gene construct encodes atherapeutic gene product, such as described the gene product of a genein Tables 1-4 and 6, or one of the following genes: SMN2, RIG-I, MDA5,LGP2, TLR7, TLR9, interferon gamma, vascular endothelial growth factor(VEGF), HER2, PSK9, Insulin receptor, CHM, growth hormone, IGF1,utrophin (UTRN), or EPO. In accordance with this embodiment, theengineered animal may be used to monitor development at different stagesor in functional biological studies where a certain protein or proteinisoform needs to be expressed only for a period of time and notconstitutively, etc.

In certain embodiments, an artificial gene construct or a vectorcomprising an artificial gene construct are used in gene therapy.

Gene Therapy

In another aspect, provided herein are artificial gene constructs orvectors comprising an artificial gene construct for use in gene therapy.The use of an artificial gene construct described herein in gene therapyallows one to regulate the amount of a functional protein produced fromthe construct depending on whether or not a compound described herein ispresent. The compound is essentially a switch that regulates the amountof functional protein produced.

In certain embodiments, an RNA transcript transcribed from an artificialgene construct that is DNA would not produce or produce substantiallyless functional protein in the absence of a compound described hereinthan the amount of functional protein produced in the presence of acompound described herein. For example, if the artificial gene constructcomprises a nucleotide sequence encoding a REMS in a 5′ splice site,which is upstream of a nucleotide sequence encoding a 3′ splice site,then less splicing would occur in the absence of the compound and thiswould result in exon skipping which would ultimately result in lessfunctional protein being produced. In a particular example, if there isan IGF1 precursor mRNA containing a REMS-controlled exon, then in theabsence of a compound described herein an exon-skipped mRNA is producedwhich cannot be translated into full length, functional IGF1. However,in the presence of a compound described herein, a full length,functional IGF1 protein is produced. The amount of the functionalprotein produced can be titrated based on dose and duration of dosing ofthe compound. In this example, the IGF1 protein is turned on and offdepending upon whether the compound is present, which may be beneficialfor a subject to maintain muscle health. Thus, the use of an artificialgene construct or a vector comprising an artificial gene construct isuseful may be useful in treating and/or preventing certain conditions ordiseases associated with genes, such as those genes described in Tables1-4 and 5, or the one of the following genes: SMN2, RIG-I, TLR7, TLR9,interferon gamma, vascular endothelial growth factor (VEGF), CHM, growthhormone, IGF1, or EPO. The conditions or diseases may include thosedescribed herein. Alternatively, in certain embodiments, an RNAtranscript transcribed from an artificial gene construct that is DNAwould not produce or would produce substantially less functional proteinin the presence of a compound described herein than the amount offunctional protein produced in the absence of a compound describedherein. For example, if the artificial gene construct comprises anucleotide sequence encoding a REMS in the middle of an exon, thenectopic splicing would occur in the presence of a compound describedherein and this would result in reduction in the production of thefunctional protein. However, in the absence of a compound describedherein, the normal splicing would occur, and the production of thefunctional protein will not be reduced. The amount of the functionalprotein produced can be titrated based on dose and duration of dosing ofthe compound.

An artificial gene construct, a vector comprising the artificial geneconstruct, or an RNA molecule comprising an artificial gene constructmodified to enable cellular uptake may be introduced into cells oradministered directly to patients. In one embodiment, an artificial geneconstruct or a vector comprising the artificial gene construct isintroduced into cells ex vivo or in vivo. In a specific embodiment, anartificial gene construct or vector is introduced into a cell(s) ex vivoand the cell(s) may be administered to a subject. Various techniquesknown to one of skill in the art may be used to introduce an artificialgene construct or vector comprising the artificial gene construct into acell(s), such as electroporation, transfection, transformation, etc. Inanother embodiment, an artificial gene construct or vector comprisingthe artificial gene construct is administered to a subject. Theartificial gene constructor vector comprising the artificial geneconstruct may be administered to a subject by any technique known to oneskilled in the art, e.g., intramuscularly, intravenously,subcutaneously, intradermally, topically, intrathecally,intraperitoneally, intratumorally, etc. In some embodiments, theartificial gene construct or vector comprising the artificial geneconstruct is administered to a subject systemically. In otherembodiments, the artificial gene construct or vector comprising theartificial gene construct is administered to a subject locally.

Altering Endogenous Genes

In another aspect, provided herein are method for altering an endogenousgene such that it contains a nucleotide sequence encoding a REMS, orcontains an additional nucleotide sequence encoding a REMS (in otherwords, a REMS not naturally found in the endogenous gene, i.e., anon-endogenous REMS). Techniques known to one of skill in the art can beused to introduce a REMS into an endogenous gene, e.g., the CRISPR-Casapproach, TALEN, or ZFN may be used. In certain embodiments, anucleotide sequence encoding an existing 5′ splice site can be replacedwith a REMS or a REMS may be inserted internally within an exon. Inintroducing a nucleotide sequence encoding a REMS into an endogenousgene, care should be taken so as not to disrupt an open reading frame orintroduce a stop codon. The introduction of a nucleotide sequenceencoding a REMS into an endogenous gene may or may not result in anamino acid change at the protein level. In certain embodiments, theintroduction of a nucleotide sequence encoding a REMS into an endogenousgene results in an amino acid change at the protein level. In someembodiments, this amino acid change is a conservative amino acidsubstitution. In other embodiments, the introduction of a nucleotidesequence encoding a REMS into an endogenous gene does not result in anamino acid change at the protein level.

Kits

In one aspect, provided herein are kits comprising, in a container, anartificial gene construct or a vector comprising an artificialconstruct. In certain embodiments, the kits further comprise a compounddescribed herein, in a separate container, and/or a negative control,such as phosphate buffered saline or a compound that does not recognizeREMS, in a separate container. In some embodiments, the kits furthercomprise primers and/or antibodies, in one or more separate containers,for assessing the production of an mRNA transcript from an artificialgene construct and/or protein production therefrom.

In another aspect, provided herein are kits comprising, in one or morecontainers, the components and/or reagents necessary to produce anartificial gene construct and/or a vector comprising an artificial geneconstruct. In another aspect, provided herein are kits comprising, inone or more containers, the components and/or reagents necessary toalter an endogenous gene so that it contains a nucleotide sequenceencoding a REMS or an additional nucleotide sequence encoding a REMS (inother words, a REMS not naturally found in the endogenous gene, i.e., anon-endogenous REMS). In some embodiments, the kits further compriseprimers and/or antibodies, in one or more separate containers, forassessing the production of an mRNA transcript from altered endogenousgene and/or protein production therefrom.

In another aspect, provided herein are kits comprising, in a container,a compound described herein, and instructions for use. In someembodiments, the kits further comprise a negative control, such asphosphate buffered saline or a compound that does not recognize REMS, ina separate container.

Examples

To describe in more detail and assist in understanding the presentdescription, the following non-limiting biological examples are offeredto more fully illustrate the scope of the description and are not to beconstrued as specifically limiting the scope thereof. Such variations ofthe present description that may be now known or later developed, whichwould be within the purview of one skilled in the art to ascertain, areconsidered to fall within the scope of the present description and ashereinafter claimed. The example below illustrates the existence of arecognition element for splicing modifier (REMS) that is important forthe recognition of a compound described herein, and the binding of sucha compound to the REMS on a precursor RNA permits or enhances thesplicing of the precursor RNA, and suggests the usefulness of the REMSin combination with a compound described herein for modulating RNAsplicing, and for modulating the amount of a gene product.

Materials and Methods

Minigene Constructs, Mutagenesis, Transfection, and End-Point RT-PCRAnalysis

The SMN2 minigene construct was prepared by PCR amplification of DNAcorresponding to a region of the SMN2 gene starting from the 5′ end ofexon 6 and ending at nucleotide 23 of exon 8 using specific primers(Forward: 5′-CGCGGATCCATAATTCCCCCACCACCTC-3′ (SEQ ID NO: 10), reverse5′-CGCGGATCCGTGCTGCTCTATGCCAGCA-3′ (SEQ ID NO: 11)). The PCR fragmentwas cloned into the BamHI site of a derivative of the original pcDNA3.1/Hygro vector which was modified as disclosed in United States PatentPublication US2005/0048549. Nucleotide alterations were introduced bysite-directed mutagenesis using the GeneArt site-directed mutagenesissystem (Life Technologies, Inc.). All mutants of SMN1 and SMN2 in thisExample were derived from the SMN2 minigene by a single nucleotide ordouble nucleotide substitution in exon 7 or intron 7. See Naryshkin etal., Science (2014) 345: 688-93, which is incorporated herein byreference, for a description of the SMN2 minigene.

For plasmid transfections, 15 ng of plasmid DNA were transfected in SMAtype 1 patient fibroblasts GM03813 in 96-well plates. Transfections werecarried out using Lipofectamine LTX (Life Technologies, Inc.) accordingto the manufacturer's instructions. To ensure uniform transfectionefficiency in cells in the 96-well plate, transfection complex for eachmutant was prepared in bulk quantities and incubated with the cells for30 minutes (reverse transfection). The total mixture of cells andtransfection complexes was then distributed into each well of the96-well plate. The plates were incubated for 16 hours in a cell cultureincubator (37° C., 5% CO₂, 100% relative humidity). Transfected cellswere then treated with Compound 702 at different concentrations (0.5%DMSO) in duplicate for 7 hours. Cells were then lysed with 50 μl ofiScript RT-qPCR Sample Preparation Reagent (Bio-Rad Laboratories, Inc).One step RT-PCR was performed using 2 μl of cell lysate and AGPATH-IDONE-STEP RT-PCR (Life Technologies, Inc.) under the following PCRconditions: Step 1: 48° C. (15 min), Step 2: 95° C. (10 min), Step 3:95° C. (30 sec), Step 4: 55° C. (30 sec), Step 5: 68° C. (1 min), thenrepeat Steps 3 to 5 for 35 cycles, then hold at 4° C. To amplify onlytranscripts derived from the transfected plasmids, PCR was performedwith the SMN Forward A primer (GATGCTGATGCTTTGGGAAGT (SEQ ID NO: 12))which hybridizes to exon 6 of both SMN1 and SMN2 and a reverse primerthat hybridizes to plasmid specific sequences. Minigene PCR productswere separated on 4% agarose E-gels, stained with ethidium bromide andvisualized using a gel imager (UVP).

Endpoint RT-PCR Analysis of Alternatively Spliced mRNAs in CulturedCells

GM03813 cells derived from a patient with SMA type I (Coriell Institute)were plated at 5,000 cells/well in 200 μl DMEM with 10% FBS in 96-wellplates, and incubated for 6 hours in a cell culture incubator (37° C.,5% CO₂, 100% relative humidity). Cells were then treated with Compound702 at different concentrations (in 0.5% DMSO) in duplicate for 24hours. After removal of the supernatant, cells were lysed in Cells-To-Ctlysis buffer (Life Technologies, Inc.). Reverse transcription wasperformed using 5 μl of cell lysate and the iScript RT enzyme kit(Bio-Rad Laboratories, Inc). PCR was performed using 5 μl of cDNA andPlatinum Taq HiFi DNA Polymerase (Life Technologies, Inc.) under thefollowing PCR conditions: Step 1: 94° C. (2 min), Step 2: 94° C. (30sec), Step 3: 55° C. (30 sec), Step 4: 68° C. (1 min), then repeat Steps2 to 4 for 33 cycles, then hold at 4° C. Alternatively spliced mRNAswere identified using primers listed in table 5. PCR products wereseparated on 2% agarose E-gels, stained with ethidium bromide andvisualized using a gel imager (UVP).

TABLE 5 Primer Name Sequence APLP2e6F1ACGGCACCATGTCAGACAA (SEQ ID NO: 13) APLP2e8R1CAACATCATTGGTTGGCAGA (SEQ ID NO: 14) STRN3e7F1ACTGCTGAAGATGGTGAAGGA (SEQ ID NO: 15) STRN3e9R1CCAGATCAGCTATCATGTCGTAG (SEQ ID NO: 16) RCC1e3F1AGACGATCTGCACTTCGCA (SEQ ID NO: 17) RCC1e5e6R1GTGAGACCTTCACCTTCTTGC (SEQ ID NO: 18) ERGIC3e6F1TGTATGGCTTCTTGGAAGTCAAT (SEQ ID NO: 19) ERGIC3e9e10R1GTAGTGGGTCATGTTGATGTTGTC (SEQ ID NO: 20) SMN ForGATGCTGATGCTTTGGGAAGT (SEQ ID NO: 12) SMN RevCGCTTCACATTCCAGATCTGTC (SEQ ID NO: 21) FOXM1 ForGTGTTGCAGCCCTCGGT (SEQ ID NO: 22) FOXM1 RevTGAACTGGAAGCAAAGGAGAA (SEQ ID NO: 23) VPS29e1F1CGGTGGTGGTGACTGAGC (SEQ ID NO: 24) VPS29e3R1GGGATGTGCAGATCTCCTAAT (SEQ ID NO: 25) GGCTe1F1AGATGAGGAGAGTTTTCTGTACTTTG (SEQ ID NO: 26) GGCTe4R1TCTCTTGATACTCCAGCGGC (SEQ ID NO: 27) PRKDC e9F1GATCTGAAGAGATATGCTGTGCC (SEQ ID NO: 28) PRKDC e12R1ACGGTCGTCACCAGTGTCTG (SEQ ID NO: 29) PRKDC e50F1GGGTCCCTAAAGATGAAGTGTTA (SEQ ID NO: 30) PRKDC e52R1ATTCACCAAAGCCTGGAAGTAT (SEQ ID NO: 31) MADD e20F1CAGAAAGTGTAAATACCCCAGTTG (SEQ ID NO: 32) MADD e22R1GCTCACACCACTGTCTGCG (SEQ ID NO: 33) LARP7 5′UTRF1CTTCCTTGGCTTCGAGTCTCTC (SEQ ID NO: 34) LARP7 e2R1CCTGTGTCCTATCATTTGTTTTCTC (SEQ ID NO: 35) LARP7 e1F1CGAAAGTAACCGAGACTATCAGG (SEQ ID NO: 36) LARP7 e4R1TTCAGTGCTTTCTTCTTCCATT (SEQ ID NO: 37) ARMCX6 e2F1CGGCACAAGTTTCAGCGAG (SEQ ID NO: 38) ARMCX6 e4R1CAGGGTGAGTAAGGATGGAGGG (SEQ ID NO: 39) GALC e4F1GGATACGAGTGGTGGTTGATG (SEQ ID NO: 40) GALC e7R1CAGAGATGGACTCCCAGAGATTA (SEQ ID NO: 41) LAMA2 e4F1GGATTTTGGAACGCTCTCTT (SEQ ID NO: 42) LAMA2 e6R1GAAATATCCTTGACCGAGTAGTAATA (SEQ ID NO: 43) ABHD10e4F1GAGAAGGTCGTGGCTCTTATTG (SEQ ID NO: 44) ABHD10e6R1GGGCTATGTAACAAGCAGTGATG (SEQ ID NO: 45) FADS2e5F1CTGCCAACTGGTGGAATCA (SEQ ID NO: 46) FADS2e8R1GATGCCGTAGAAAGGGATGTAG (SEQ ID NO: 47) DIAPH3e10F1TCAATGCCCTGGTTACATCTC (SEQ ID NO: 48) DIAPH3e13R1ACAATCTGGGATACACACTCATCA (SEQ ID NO: 49) PDIA3e3F1CTGCCAACACTAACACCTGTAATA (SEQ ID NO: 50) PDIA3e7R1AGTCCTTGCCCTGTATCAAATC (SEQ ID NO: 51) FN1e34F1GCTCATCCGTGGTTGTATCAG (SEQ ID NO: 52) FN1e36R1GATCGTCTCAGTCTTGGTTCTCC (SEQ ID NO: 53) PARP1e20F1AGTGCCAACTACTGCCATACG (SEQ ID NO: 54) PARP1ee23R1AATCCTTTCTGAGGTGGTTTAGT (SEQ ID NO: 55) COL1Ae2F1CAAGGTGTTGTGCGATGACG (SEQ ID NO: 56) COL1Ae6R1GGTTGATTTCTCATCATAGCCATAAG (SEQ ID NO: 57) COLA1e7F1CCTCTGGTCCTCGTGGTCTC (SEQ ID NO: 58) COL1Ae12R1CCATCCAAACCACTGAAACC (SEQ ID NO: 59) COLA1e27F1GGTCCTGCTGGCAAAGATG (SEQ ID NO: 60) COLA1e31R1GCTCGCCAGGGAAACCTC (SEQ ID NO: 61) COLA1e31F1AGGCGAGAGAGGTTTCCCT (SEQ ID NO: 62) COLA1e33e34R1GGACCACTTTCACCCTTGTCA (SEQ ID NO: 63) COLA1e47F1GGGCGACAGAGGCATAAAG (SEQ ID NO: 64) COLA1e48R1TCACGGTCACGAACCACATT (SEQ ID NO: 65) COL1A2e20F1CAAAGGAGAGAGCGGTAACAAG (SEQ ID NO: 66) COL1A2e22R1AAGACCACGAGAACCAGGACTA (SEQ ID NO: 67) COL1A2e22F1CCTGGTTCTCGTGGTCTTC (SEQ ID NO: 68) COL1A2e24e25R1GCCGACAGGACCTTCTTT (SEQ ID NO: 69) COL1A2e29F1TGGCAAACCAGGAGAAAGG (SEQ ID NO: 70) COL1A2e31R1AAGGACCTCGGCTTCCAATA (SEQ ID NO: 71) COL3A1e7e8F1GGCAAGCTGGTCCTTCAG (SEQ ID NO: 72) COL3A1e11R1GGAGCACCTGTTTCACCCT (SEQ ID NO: 73) COL3A1e45F1TGACAAAGGTGAAACAGGTGAAC (SEQ ID NO: 74) COL3A1e47R1GTCCACTGGGTCCAACAGGT (SEQ ID NO: 75) COL5A2e10e11F1AATGGGTCCGATTGGTTCAC (SEQ ID NO: 76) COL52Ae16R1CAAGTCTCCCTCTCTCTCCTGG (SEQ ID NO: 77) COL52Ae30F1GGTGAAAGAGGAGAACAAGGA (SEQ ID NO: 78) COL52Ae33R1TCACCAGGGAGTCCAGTTAT (SEQ ID NO: 79) COL52Ae33F1AGAACCTGGGATAACTGGACTC (SEQ ID NO: 80) COL5A2e35e36R1AGACCTCTTGCACCATCATTT (SEQ ID NO: 81) COL5A2e33F1AGGGAATGGCTGGAGGA (SEQ ID NO: 82) COL5A2e36R1CCCAAAGGACCTGGAAGAC (SEQ ID NO: 83) COL5A2e48F1AGGACCTCGTGGTGACAAAG (SEQ ID NO: 84) COL5A2e50R1GCCCAGGGTTTCCTTCTTTA (SEQ ID NO: 85) SMNe4F1GATGAAAGTGAGAACTCCAGGTC (SEQ ID NO: 86) SMNe6R1CAAAGCATCAGCATCATCAAG (SEQ ID NO: 87)

Results

SMN1 mutant C6 (i.e., single substitution of original nucleotide T6 ofexon 7 to C6) showed compound-dependent increased inclusion of exon 7,demonstrating that the C6/T is not the working site of the compound(FIG. 2A).

The initial work was focused on investigating the secondary structure ofTSL2 (terminal stem loop 2, a predicted secondary structure in SMN2, notfound in other responsive genes) as a potential working site of thecompounds (FIG. 2B). Several mutations in that region were introduced tostudy the effect of the compounds on these mutants. One of the mutantsparticularly, SMN2 T43A, A51T (FIG. 3A), resulted in enhanced inclusionof exon 7 compare to wild-type SMN. However this mutant was resistant tocompound-dependent inclusion of exon 7. No further enhancement of exon 7inclusion could be achieved above baseline splicing in this mutant(FIGS. 3B, 4A, 4B), and the effect appeared to be driven by A51 mutant,since the effect was more pronounced with A51T single nucleotide changemutant (FIGS. 4A, 4B).

Additional mutants confirmed the functional role of a recognitionelement for splicing modifier (REMS) in SMN1 and SMN2 (FIG. 5A). TheSMN2 G51, SMN2 C43G51 and SMN2 G43C51 mutants further demonstrated thefunctional role of A51, with decreased (G51, C43G51) inclusion of exon 7compared to wild-type SMN2, (compare DMSO lanes), these mutants did notrespond to compound (FIG. 5B). The SMN2 C53, SMN2 T53 and SMN2 G41C53mutants further demonstrated the functional role of G53, with decreased(T53, G41C53) or increased (G41C53) inclusion of exon 7 compared towild-type SMN2, (compare DMSO lanes), these mutants did not respond tocompound FIG. 5B).

In addition, the activity of the compound on splicing is maintained inmutations outside of the REMS (FIG. 6). The SMN2 A50T, SMN2 C44G50, SMN2G44C50, SMN2 A44T50 mutants with either a decreased or an increasedinclusion of exon 7 compared to wild-type SMN2, (compare DMSO lanes),showed compound-dependent increased inclusion of exon 7, demonstratingthat position is not the interaction (direct or functional) site of thecompound (FIG. 6).

Besides, testing the alternatively spliced mRNAs of additional genesalso confirmed the existence of a consensus REMS. Testing results ofalternatively spliced mRNAs are shown in Table 6 (affected genes), Table7 (all genes tested) and FIGS. 7A-7L (correspond to Table 6), and arealso summarized below:

For SMN2, the RT-PCR data showed that AGGAguaagu (SEQ ID NO: 88)sequence motif resulted in a compound-dependent increase in theinclusion of exon 7 of SMN2 (increase from 40% to 100%.

For FOXM1, ATCAgtaagt (SEQ ID NO: 89) sequence motif resulted inselectivity against the inclusion of exon 7A of FOXM1 in the presence ofthe compound. Only 10% increase in exon 7A inclusion was observed.However the upstream 5′ alternative splicing site within exon 7A ofFOXM1 with the sequence motif of ATGAgtaagt (SEQ ID NO: 90) (30nucleotides downstream from the start of exon 7A) resulted in increasedinclusion of exon 7A ΔC up to 90%.

For APLP2, ATGA (SEQ ID NO: 91) sequence motif resulted in acompound-dependent increase in the inclusion of exon 7 of APLP2(increase from 10% to 30%).

For GGCT, ATGA (SEQ ID NO: 91) sequence motif resulted in acompound-dependent increase in the inclusion of exon 2 of GGCT (increasefrom 40% to 95%).

For ABHD10, ATGA (SEQ ID NO: 91) sequence motif resulted in acompound-dependent increase in the inclusion of exon 5 of ABHD10(increase from 10% to 30%).

For STRN3, AAGA (SEQ ID NO: 92) sequence motif resulted in acompound-dependent increase in the inclusion of exon 8 of STRN3(increase from 10% to 100%).

For VPS29, CAGA (SEQ ID NO: 93) sequence motif resulted in acompound-dependent increase in the inclusion of exon 2 of VPS29. Notablythis exon consist of only 12 nucleotides.

For ERGIC3, GAGA (SEQ ID NO: 94) sequence motif resulted in acompound-dependent increase in the inclusion of exon 8 of ERGIC3(increase from 0% to 10%).

For MADD, CAGA (SEQ ID NO: 93) sequence motif resulted in acompound-dependent increase in the inclusion of exon 21 of MADD(increase from 0% to 5%).

For LARP7, CGGA (SEQ ID NO: 95) sequence motif resulted in acompound-dependent increase in the inclusion of part of exon 1 of LARP7(increase from 0% to 10%).

For LARP7, AAGA (SEQ ID NO: 92) sequence motif resulted in acompound-dependent increase in the inclusion of exon 2 of LARP7(increase from 5% to 40%).

For COL1A1, AAGA (SEQ ID NO: 92) sequence motif result in acompound-dependent increase in the inclusion of exon 30 of COL1A1(increase from 60% to 90%).

TABLE 6 Alternative splicing results of affected genes. % Inclusion %of Exon Ser Compound Inclusion with # Gene Exon Sequence Tested of ExonCompound 1 SMN2 exon 7 AGGAgtaagt Compound 702 40 100 (SEQ ID NO: 96) 2FOXM1 exon 7A (114 ATCAgtaagt Compound 702 0 10 nucleotides)(SEQ ID NO: 89) 3 FOXM1 exon 7A □C ATGAgtaagt Compound 702 0 90(34 nucleotides)  (SEQ ID NO: 90) 4 APLP2 exon 7 ATGAgtaagt Compound 70210 30 (SEQ ID NO: 90) 5 GGCT exon 2 ATGAgtaggt Compound 702 40 95(SEQ ID NO: 97) 6 ABHD10 exon 5 ATGAgtatgt Compound 702 10 30(SEQ ID NO: 98) 7 STRN3 exon 8 AAGAgtaagt Compound 702 10 100(SEQ ID NO: 99) 8 VPS29 exon 2 CAGAgtaagt Compound 702 40 100(SEQ ID NO: 100) 9 ERGIC3 exon 8 GAGAgtaagt Compound 702 0 10(SEQ ID NO: 101) 10 MADD exon 21 CAGAgtaagg Compound 702 0 5(SEQ ID NO: 102) 11 LARP7 exon 1 CGGAgtaagt Compound 702 0 10(SEQ ID NO: 103) 12 LARP7 exon 2 AAGAgtaaga Compound 702 10 40(SEQ ID NO: 104) 13 COL1A1 exon 30 AAGAgtaagt Compound 702 60 90(SEQ ID NO: 99)

TABLE 7 Alternative splicing of all genes tested. % Inclusion % of ExonSer Compound Inclusion with # Gene Exon Sequence Tested of Exon Compound1 SMN2 exon 7 AGGAgtaagt Compound 702 40 100 (SEQ ID NO: 96) 2 FOXM1exon 7A ATCAgtaagt Compound 702 0 10 (114 nucleotides) (SEQ ID NO: 89) 3FOXM1 exon 7A □C ATGAgtaagt Compound 702 0 90 (34 nucleotides)(SEQ ID NO: 90) 5 APLP2 exon 7 ATGAgtaagt Compound 702 10 30(SEQ ID NO: 90) 8 GGCT exon 2 ATGAgtaggt Compound 702 40 95(SEQ ID NO: 97) 18 ABHD10 exon 5 ATGAgtatgt Compound 702 20 80(SEQ ID NO: 98) 4 STRN3 exon 8 AAGAgtaagt Compound 702 10 100(SEQ ID NO: 99) 6 VP529 exon 2 CAGAgtaagt Compound 702 40 100(SEQ ID NO: 100) 7 ERGIC3 exon 8 GAGAgtaagt Compound 702 0 10(SEQ ID NO: 101) 15 MADD exon 21 CAGAgtaagg Compound 702 0 5(SEQ ID NO: 102) 16 LARP 7 exon 1 CGGAgtaagt Compound 702 0 10(SEQ ID NO: 103) 17 LARP 7 exon 2 AAGAgtaaga Compound 702 10 40(SEQ ID NO: 104) 10 ARMCX6 exon 3 TAGAgtatga Compound 702 0 no change(SEQ ID NO: 105) 11 GALC exon 5 TGGAgttagt Compound 702 90 no change(SEQ ID NO: 106) 12 LAMA2 exon 5 AAGAgtaagt Compound 702 100 no change(SEQ ID NO: 99) 13 PRKDC exon 11 AGGAgtatgt Compound 702 100 no change(SEQ ID NO: 107) 14 PRKDC exon 51 GCGAgtacgt Compound 702 100 no change(SEQ ID NO: 108) 9 RCC 1 exon 4 AGAGgtaaga Compound 702 90 no change(SEQ ID NO: 109) 19 FADS2 exon 6 CTGAgtaagt Compound 702 100 no change(SEQ ID NO: 110) 20 DIAPH3 exon 11 TTGAatatcc Compound 702 100 no change(SEQ ID NO: 111) 21 FN1 exon 35 GAGAgtaagt Compound 702 100 no change(SEQ ID NO: 101) 22 PARP1 exon 22 ACGAgtatcc Compound 702 100 no change(SEQ ID NO: 112) 23 COL1A1 exon 5 AGGAgtaagt Compound 702 0 no change(SEQ ID NO: 96) 24 COL1A1 exon 11 CAGAgtgagt Compound 702 100 no change(SEQ ID NO: 113) 25 COL1A1 exon 30 AAGAgtaagt Compound 702 60 90(SEQ ID NO: 99) 26 COL1A1 exon 32 CAGAgtaagt Compound 702 90 no change(SEQ ID NO: 100) 27 COL1A1 exon 46 CCGAgtaagt Compound 702 100 no change(SEQ ID NO: 114) 28 COL1A2 exon 21 GAGAgtaggt Compound 702 100 no change(SEQ ID NO: 115) 29 COL1A2 exon 22 CAGAgtaagt Compound 702 100 no change(SEQ ID NO: 100) 30 COL1A2 exon 30 AAGAgtaagt Compound 702 100 no change(SEQ ID NO: 99) 31 COL3A1 exon 10 CAGAgtaagt Compound 702 100 no change(SEQ ID NO: 100) 32 COL3A1 exon 46 CAGAgtaagt Compound 702 100 no change(SEQ ID NO: 100) 33 COL5A2 exon 13 CCGAgtaagt Compound 702 100 no change(SEQ ID NO: 114) 34 COL5A2 exon 32 TAGAgtaagt Compound 702 100 no change(SEQ ID NO: 116) 35 COL5A2 exon 34 CAGAgtaagt Compound 702 100 no change(SEQ ID NO: 100) 36 COL5A2 exon 35 AAGAgtaagt Compound 702 100 no change(SEQ ID NO: 99) 37 COL5A2 exon 49 AAGAgtaagt Compound 702 90 no change(SEQ ID NO: 99) 38 SMN2 exon 5 ACCAgtaagt Compound 702 50 no change(SEQ ID NO: 117)

It will be appreciated that, although specific embodiments of theinvention have been described herein for purposes of illustration, theinvention described herein is not to be limited in scope by the specificembodiments herein disclosed. These embodiments are intended asillustrations of several aspects of the invention. Any equivalentembodiments are intended to be within the scope of this invention.Indeed, various modifications of the invention in addition to thoseshown and described herein will become apparent to those skilled in theart from the foregoing description, which modification also intended tobe within the scope of this invention.

All references cited herein are incorporated herein by reference intheir entirety and for all purposes to the same extent as if eachindividual publication or patent or patent application was specificallyand individually indicated to be incorporated by reference in itsentirety for all purposes.

1.-23. (canceled)
 24. A method for gene therapy, comprisingadministering to a human subject an artificial gene construct or avector comprising an artificial gene construct, wherein the artificialgene construct comprises: (A) a DNA sequence encoding exons and one, twoor more introns, wherein a nucleotide sequence encoding a 5′ splicesite, which is upstream of a nucleotide sequence encoding a branch pointand a nucleotide sequence encoding a 3′ splice site, contains anucleotide sequence encoding a recognition element for splicing modifier(REMS), wherein the REMS comprises the sequence GAgtrngn (SEQ ID NO:5),wherein r is A or G and n is any nucleotide; or (B) an RNA sequencecomprising exons and one, two or more introns, wherein a 5′ splice site,which is upstream of a branch point and a 3′ splice site, contains aREMS, wherein the REMS comprises the sequence GAgurngn (SEQ ID NO:1),wherein r is A or G and n is any nucleotide.
 25. A method for genetherapy, comprising administering to a human subject cells transfectedor transduced with an artificial gene construct or a vector comprisingan artificial gene construct, wherein the artificial gene constructcomprises: (A) a DNA sequence encoding exons and one, two or moreintrons, wherein a nucleotide sequence encoding a 5′ splice site, whichis upstream of a nucleotide sequence encoding a branch point and anucleotide sequence encoding a 3′ splice site, contains a nucleotidesequence encoding a recognition element for splicing modifier (REMS),wherein the REMS comprises the sequence GAgtrngn (SEQ ID NO:5), whereinr is A or G and n is any nucleotide; or (B) an RNA sequence comprisingexons and one, two or more introns, wherein a 5′ splice site, which isupstream of a branch point and a 3′ splice site, contains a REMS,wherein the REMS comprises the sequence GAgurngn (SEQ ID NO:1), whereinr is A or G and n is any nucleotide.
 26. A method for regulating theamount of a functional protein produced by a human subject, the methodcomprising: (a) administering an artificial gene construct or a vectorcomprising the artificial gene construct to the subject; and (b)administering a compound of Formula (I) or a form thereof to thesubject, wherein the artificial gene construct comprises: (A) a DNAsequence encoding exons and one, two or more introns, wherein anucleotide sequence encoding a 5′ splice site, which is upstream of anucleotide sequence encoding a branch point and a nucleotide sequenceencoding a 3′ splice site, contains a nucleotide sequence encoding arecognition element for splicing modifier (REMS); or (B) an RNA sequencecomprising exons and one, two or more introns, wherein a 5′ splice site,which is upstream of a branch point and a 3′ splice site, contains aREMS, wherein the REMS comprises the sequence GAgurngn (SEQ ID NO:1),wherein r is A or G and n is any nucleotide, and wherein Formula (I) is:

wherein: w₁ and w₅ are independently C—R_(a) or N; w₂ is C—R_(b) or N;w₃, w₄ and w₇ are independently C—R₁, C—R₂, C—R_(a) or N; w₆ is C—R₁,C—R₂, C—R_(c) or N; wherein one of w₃, w₄, w₆ and w₇ is C—R₁ and oneother of w₃, w₄, w₆ and w₇ is C—R₂, provided that, when w₃ is C—R₁, thenw₆ is C—R₂ and w₄ and w₇ are independently C—R_(a) or N; or, when w₃ isC—R₂, then w₆ is C—R₁ and w₄ and w₇ are independently C—R_(a) or N; or,when w₄ is C—R₁, then w₇ is C—R₂ and w₃ is C—R_(a) or N and w₆ isC—R_(c) or N; or, when w₄ is C—R₂, then w₇ is C—R₁ and w₃ is C—R_(a) orN and w₆ is C—R_(c) or N; and, wherein any one, two or three of w₁, w₂,w₃, w₄, w₅, w₆ and w₇ may optionally be N; R₁ is C₁₋₈alkyl, amino,C₁₋₈alkyl-amino, (C₁₋₈alkyl)₂-amino, C₁₋₈alkoxy-C₁₋₈alkyl-amino,(C₁₋₈alkoxy-C₁₋₈alkyl)₂-amino, (C₁₋₈alkoxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino,amino-C₁₋₈alkyl, C₁₋₈alkyl-amino-C₁₋₈alkyl,(C₁₋₈alkyl)₂-amino-C₁₋₈alkyl, C₁₋₈alkoxy-C₁₋₈alkyl-amino-C₁₋₈alkyl,(C₁₋₈alkoxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,(C₁₋₈alkoxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl, amino-C₁₋₈alkyl-amino,(amino-C₁₋₈alkyl)₂-amino, (amino-C₁₋₈alkyl)(C₁₋₈alkyl)amino,C₁₋₈alkyl-amino-C₁₋₈alkyl-amino, (C₁₋₈alkyl-amino-C₁₋₈alkyl)₂-amino,(C₁₋₈alkyl-amino-C₁₋₈alkyl)(C₁₋₈alkyl)amino,(C₁₋₈alkyl)₂-amino-C₁₋₈alkyl-amino,[(C₁₋₈alkyl)₂-amino-C₁₋₈alkyl](C₁₋₈alkyl)amino, amino-C₁₋₈alkoxy,C₁₋₈alkyl-amino-C₁₋₈alkoxy, (C₁₋₈alkyl)₂-amino-C₁₋₈alkoxy,C₁₋₈alkoxy-C₁₋₈alkyl-amino-C₁₋₈alkoxy,C₁₋₈alkoxy-C₁₋₈alkyl-amino-C₁₋₈alkoxy,(C₁₋₈alkoxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkoxy, amino-C₂₋₈alkenyl,C₁₋₈alkyl-amino-C₂₋₈alkenyl, (C₁₋₈alkyl)₂-amino-C₂₋₈alkenyl,amino-C₂₋₈alkynyl, C₁₋₈alkyl-amino-C₂₋₈alkynyl,(C₁₋₈alkyl)₂-amino-C₂₋₈alkynyl, halo-C₁₋₈alkyl-amino,(halo-C₁₋₈alkyl)₂-amino, (halo-C₁₋₈alkyl)(C₁₋₈alkyl)amino,hydroxy-C₁₋₈alkyl, hydroxy-C₁₋₈alkoxy-C₁₋₈alkyl,hydroxy-C₁₋₈alkyl-amino, (hydroxy-C₁₋₈alkyl)₂-amino,(hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino, hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkyl,(hydroxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,(hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl,hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkoxy,(hydroxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkoxy,(hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkoxy,hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkyl-amino,(hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkyl)₂-amino,(hydroxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl-amino,(hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkyl)(C₁₋₈alkyl)amino,(hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl-amino,[(hydroxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl](C₁₋₈alkyl)amino,[(hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl](C₁₋₈alkyl)amino,heterocyclyl, heterocyclyl-C₁₋₈alkyl, heterocyclyl-C₁₋₈alkoxy,heterocyclyl-amino, (heterocyclyl)(C₁₋₈alkyl)amino,heterocyclyl-amino-C₁₋₈alkyl, heterocyclyl-C₁₋₈alkyl-amino,(heterocyclyl-C₁₋₈alkyl)₂-amino,(heterocyclyl-C₁₋₈alkyl)(C₁₋₈alkyl)amino,heterocyclyl-C₁₋₈alkyl-amino-C₁₋₈alkyl,(heterocyclyl-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,(heterocyclyl-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl, heterocyclyl-oxy,heterocyclyl-carbonyl, heterocyclyl-carbonyl-oxy, C₃₋₁₄cycloalkyl,aryl-C₁₋₈alkyl-amino, (aryl-C₁₋₈alkyl)₂-amino,(aryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino, aryl-C₁₋₈alkyl-amino-C₁₋₈alkyl,(aryl-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,(aryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl, heteroaryl,heteroaryl-C₁₋₈alkyl, heteroaryl-C₁₋₈alkoxy, heteroaryl-amino,heteroaryl-C₁₋₈alkyl-amino, (heteroaryl-C₁₋₈alkyl)₂-amino,(heteroaryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino,heteroaryl-C₁₋₈alkyl-amino-C₁₋₈alkyl,(heteroaryl-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl or(heteroaryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl; wherein, each instanceof heterocyclyl, C₃₋₁₄cycloalkyl, aryl and heteroaryl is optionallysubstituted with one, two or three R₃ substituents and optionally, withone additional R₄ substituent; or, wherein, each instance ofheterocyclyl, C₃₋₁₄cycloalkyl, aryl and heteroaryl is optionallysubstituted with one, two, three or four R₃ substituents; R₂ is aryl,aryl-amino, aryl-amino-carbonyl, heterocyclyl, heteroaryl orheteroaryl-amino; wherein, each instance of aryl, heterocyclyl andheteroaryl is optionally substituted with one, two or three R₆substituents and optionally, with one additional R₇ substituent; R_(a)is, in each instance, independently selected from hydrogen, halogen,C₁₋₈alkyl or deuterium; R_(b) is hydrogen, halogen, C₁₋₈alkyl,C₁₋₈alkoxy or deuterium; R_(c) is hydrogen, halogen, C₁₋₈alkyl ordeuterium; R₃ is, in each instance, independently selected from cyano,halogen, hydroxy, oxo, C₁₋₈alkyl, halo-C₁₋₈alkyl, C₁₋₈alkyl-carbonyl,C₁₋₈alkoxy, halo-C₁₋₈alkoxy, C₁₋₈alkoxy-C₁₋₈alkyl, C₁₋₈alkoxy-carbonyl,amino, C₁₋₈alkyl-amino, (C₁₋₈alkyl)₂-amino, amino-C₁₋₈alkyl,C₁₋₈alkyl-amino-C₁₋₈alkyl, (C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,amino-C₁₋₈alkyl-amino, C₁₋₈alkyl-amino-C₁₋₈alkyl-amino,(C₁₋₈alkyl-amino-C₁₋₈alkyl)₂-amino, (C₁₋₈alkyl)₂-amino-C₁₋₈alkyl-amino,[(C₁₋₈alkyl)₂-amino-C₁₋₈alkyl]₂-amino,(C₁₋₈alkyl-amino-C₁₋₈alkyl)(C₁₋₈alkyl)amino,[(C₁₋₈alkyl)₂-amino-C₁₋₈alkyl](C₁₋₈alkyl)amino,C₁₋₈alkoxy-C₁₋₈alkyl-amino, (C₁₋₈alkoxy-C₁₋₈alkyl)₂-amino,(C₁₋₈alkoxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino, C₁₋₈alkyl-carbonyl-amino,C₁₋₈alkoxy-carbonyl-amino, hydroxy-C₁₋₈alkyl,hydroxy-C₁₋₈alkoxy-C₁₋₈alkyl, hydroxy-C₁₋₈alkyl-amino,(hydroxy-C₁₋₈alkyl)₂-amino or (hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino; R₄ isC₃₋₁₄cycloalkyl, C₃₋₁₄cycloalkyl-C₁₋₈alkyl, C₃₋₁₄cycloalkyl-amino,aryl-C₁₋₈alkyl, aryl-C₁₋₈alkoxy-carbonyl, aryl-sulfonyloxy-C₁₋₈alkyl,heterocyclyl or heterocyclyl-C₁₋₈alkyl; wherein, each instance ofC₃₋₁₄cycloalkyl, aryl and heterocyclyl is optionally substituted withone, two or three R₅ substituents; R₅ is, in each instance,independently selected from halogen, hydroxy, cyano, nitro, C₁₋₈alkyl,halo-C₁₋₈alkyl, C₁₋₈alkoxy, halo-C₁₋₈alkoxy, amino, C₁₋₈alkyl-amino,(C₁₋₈alkyl)₂-amino or C₁₋₈alkyl-thio; R₆ is, in each instance,independently selected from halogen, hydroxy, cyano, nitro, C₁₋₈alkyl,C₂₋₈alkenyl, halo-C₁₋₈alkyl, hydroxy-C₁₋₈alkyl, C₁₋₈alkoxy,halo-C₁₋₈alkoxy, C₁₋₈alkoxy-C₁₋₈alkyl, amino, C₁₋₈alkyl-amino,(C₁₋₈alkyl)₂-amino or C₁₋₈alkyl-thio; and, R₇ is C₃₋₁₄cycloalkyl,C₃₋₁₄cycloalkyl-oxy, aryl, heterocyclyl or heteroaryl.
 27. The method ofclaim 24, wherein the method further comprises administering to thesubject a compound of Formula (I) or a form thereof, and wherein Formula(I) is:

wherein: w₁ and w₅ are independently C—R_(a) or N; w₂ is C—R_(b) or N;w₃, w₄ and w₇ are independently C—R₁, C—R₂, C—R_(a) or N; w₆ is C—R₁,C—R₂, C—R_(c) or N; wherein one of w₃, w₄, w₆ and w₇ is C—R₁ and oneother of w₃, w₄, w₆ and w₇ is C—R₂, provided that, when w₃ is C—R₁, thenw₆ is C—R₂ and w₄ and w₇ are independently C—R_(a) or N; or, when w₃ isC—R₂, then w₆ is C—R₁ and w₄ and w₇ are independently C—R_(a) or N; or,when w₄ is C—R₁, then w₇ is C—R₂ and w₃ is C—R_(a) or N and w₆ isC—R_(c) or N; or, when w₄ is C—R₂, then w₇ is C—R₁ and w₃ is C—R_(a) orN and w₆ is C—R_(c) or N; and, wherein any one, two or three of w₁, w₂,w₃, w₄, w₅, w₆ and w₇ may optionally be N; R₁ is C₁₋₈alkyl, amino,C₁₋₈alkyl-amino, (C₁₋₈alkyl)₂-amino, C₁₋₈alkoxy-C₁₋₈alkyl-amino,(C₁₋₈alkoxy-C₁₋₈alkyl)₂-amino, (C₁₋₈alkoxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino,amino-C₁₋₈alkyl, C₁₋₈alkyl-amino-C₁₋₈alkyl,(C₁₋₈alkyl)₂-amino-C₁₋₈alkyl, C₁₋₈alkoxy-C₁₋₈alkyl-amino-C₁₋₈alkyl,(C₁₋₈alkoxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,(C₁₋₈alkoxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl, amino-C₁₋₈alkyl-amino,(amino-C₁₋₈alkyl)₂-amino, (amino-C₁₋₈alkyl)(C₁₋₈alkyl)amino,C₁₋₈alkyl-amino-C₁₋₈alkyl-amino, (C₁₋₈alkyl-amino-C₁₋₈alkyl)₂-amino,(C₁₋₈alkyl-amino-C₁₋₈alkyl)(C₁₋₈alkyl)amino,(C₁₋₈alkyl)₂-amino-C₁₋₈alkyl-amino,[(C₁₋₈alkyl)₂-amino-C₁₋₈alkyl](C₁₋₈alkyl)amino, amino-C₁₋₈alkoxy,C₁₋₈alkyl-amino-C₁₋₈alkoxy, (C₁₋₈alkyl)₂-amino-C₁₋₈alkoxy,C₁₋₈alkoxy-C₁₋₈alkyl-amino-C₁₋₈alkoxy,C₁₋₈alkoxy-C₁₋₈alkyl-amino-C₁₋₈alkoxy,(C₁₋₈alkoxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkoxy, amino-C₂₋₈alkenyl,C₁₋₈alkyl-amino-C₂₋₈alkenyl, (C₁₋₈alkyl)₂-amino-C₂₋₈alkenyl,amino-C₂₋₈alkynyl, C₁₋₈alkyl-amino-C₂₋₈alkynyl,(C₁₋₈alkyl)₂-amino-C₂₋₈alkynyl, halo-C₁₋₈alkyl-amino,(halo-C₁₋₈alkyl)₂-amino, (halo-C₁₋₈alkyl)(C₁₋₈alkyl)amino,hydroxy-C₁₋₈alkyl, hydroxy-C₁₋₈alkoxy-C₁₋₈alkyl,hydroxy-C₁₋₈alkyl-amino, (hydroxy-C₁₋₈alkyl)₂-amino,(hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino, hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkyl,(hydroxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,(hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl,hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkoxy,(hydroxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkoxy,(hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkoxy,hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkyl-amino,(hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkyl)₂-amino,(hydroxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl-amino,(hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkyl)(C₁₋₈alkyl)amino,(hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl-amino,[(hydroxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl](C₁₋₈alkyl)amino,[(hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl](C₁₋₈alkyl)amino,heterocyclyl, heterocyclyl-C₁₋₈alkyl, heterocyclyl-C₁₋₈alkoxy,heterocyclyl-amino, (heterocyclyl)(C₁₋₈alkyl)amino,heterocyclyl-amino-C₁₋₈alkyl, heterocyclyl-C₁₋₈alkyl-amino,(heterocyclyl-C₁₋₈alkyl)₂-amino,(heterocyclyl-C₁₋₈alkyl)(C₁₋₈alkyl)amino,heterocyclyl-C₁₋₈alkyl-amino-C₁₋₈alkyl,(heterocyclyl-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,(heterocyclyl-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl, heterocyclyl-oxy,heterocyclyl-carbonyl, heterocyclyl-carbonyl-oxy, C₃₋₁₄cycloalkyl,aryl-C₁₋₈alkyl-amino, (aryl-C₁₋₈alkyl)₂-amino,(aryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino, aryl-C₁₋₈alkyl-amino-C₁₋₈alkyl,(aryl-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,(aryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl, heteroaryl,heteroaryl-C₁₋₈alkyl, heteroaryl-C₁₋₈alkoxy, heteroaryl-amino,heteroaryl-C₁₋₈alkyl-amino, (heteroaryl-C₁₋₈alkyl)₂-amino,(heteroaryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino,heteroaryl-C₁₋₈alkyl-amino-C₁₋₈alkyl,(heteroaryl-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl or(heteroaryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl; wherein, each instanceof heterocyclyl, C₃₋₁₄cycloalkyl, aryl and heteroaryl is optionallysubstituted with one, two or three R₃ substituents and optionally, withone additional R₄ substituent; or, wherein, each instance ofheterocyclyl, C₃₋₁₄cycloalkyl, aryl and heteroaryl is optionallysubstituted with one, two, three or four R₃ substituents; R₂ is aryl,aryl-amino, aryl-amino-carbonyl, heterocyclyl, heteroaryl orheteroaryl-amino; wherein, each instance of aryl, heterocyclyl andheteroaryl is optionally substituted with one, two or three R₆substituents and optionally, with one additional R₇ substituent; R_(a)is, in each instance, independently selected from hydrogen, halogen,C₁₋₈alkyl or deuterium; R_(b) is hydrogen, halogen, C₁₋₈alkyl,C₁₋₈alkoxy or deuterium; R_(c) is hydrogen, halogen, C₁₋₈alkyl ordeuterium; R₃ is, in each instance, independently selected from cyano,halogen, hydroxy, oxo, C₁₋₈alkyl, halo-C₁₋₈alkyl, C₁₋₈alkyl-carbonyl,C₁₋₈alkoxy, halo-C₁₋₈alkoxy, C₁₋₈alkoxy-C₁₋₈alkyl, C₁₋₈alkoxy-carbonyl,amino, C₁₋₈alkyl-amino, (C₁₋₈alkyl)₂-amino, amino-C₁₋₈alkyl,C₁₋₈alkyl-amino-C₁₋₈alkyl, (C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,amino-C₁₋₈alkyl-amino, C₁₋₈alkyl-amino-C₁₋₈alkyl-amino,(C₁₋₈alkyl-amino-C₁₋₈alkyl)₂-amino, (C₁₋₈alkyl)₂-amino-C₁₋₈alkyl-amino,[(C₁₋₈alkyl)₂-amino-C₁₋₈alkyl]₂-amino,(C₁₋₈alkyl-amino-C₁₋₈alkyl)(C₁₋₈alkyl)amino,[(C₁₋₈alkyl)₂-amino-C₁₋₈alkyl](C₁₋₈alkyl)amino,C₁₋₈alkoxy-C₁₋₈alkyl-amino, (C₁₋₈alkoxy-C₁₋₈alkyl)₂-amino,(C₁₋₈alkoxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino, C₁₋₈alkyl-carbonyl-amino,C₁₋₈alkoxy-carbonyl-amino, hydroxy-C₁₋₈alkyl,hydroxy-C₁₋₈alkoxy-C₁₋₈alkyl, hydroxy-C₁₋₈alkyl-amino,(hydroxy-C₁₋₈alkyl)₂-amino or (hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino; R₄ isC₃₋₁₄cycloalkyl, C₃₋₁₄cycloalkyl-C₁₋₈alkyl, C₃₋₁₄cycloalkyl-amino,aryl-C₁₋₈alkyl, aryl-C₁₋₈alkoxy-carbonyl, aryl-sulfonyloxy-C₁₋₈alkyl,heterocyclyl or heterocyclyl-C₁₋₈alkyl; wherein, each instance ofC₃₋₁₄cycloalkyl, aryl and heterocyclyl is optionally substituted withone, two or three R₅ substituents; R₅ is, in each instance,independently selected from halogen, hydroxy, cyano, nitro, C₁₋₈alkyl,halo-C₁₋₈alkyl, C₁₋₈alkoxy, halo-C₁₋₈alkoxy, amino, C₁₋₈alkyl-amino,(C₁₋₈alkyl)₂-amino or C₁₋₈alkyl-thio; R₆ is, in each instance,independently selected from halogen, hydroxy, cyano, nitro, C₁₋₈alkyl,C₂₋₈alkenyl, halo-C₁₋₈alkyl, hydroxy-C₁₋₈alkyl, C₁₋₈alkoxy,halo-C₁₋₈alkoxy, C₁₋₈alkoxy-C₁₋₈alkyl, amino, C₁₋₈alkyl-amino,(C₁₋₈alkyl)₂-amino or C₁₋₈alkyl-thio; and, R₇ is C₃₋₁₄cycloalkyl,C₃₋₁₄cycloalkyl-oxy, aryl, heterocyclyl or heteroaryl.
 28. The method ofclaim 25, wherein the method further comprises administering to thesubject a compound of Formula (I) or a form thereof, and wherein Formula(I) is:

wherein: w₁ and w₅ are independently C—R_(a) or N; w₂ is C—R_(b) or N;w₃, w₄ and w₇ are independently C—R₁, C—R₂, C—R_(a) or N; w₆ is C—R₁,C—R₂, C—R_(c) or N; wherein one of w₃, w₄, w₆ and w₇ is C—R₁ and oneother of w₃, w₄, w₆ and w₇ is C—R₂, provided that, when w₃ is C—R₁, thenw₆ is C—R₂ and w₄ and w₇ are independently C—R_(a) or N; or, when w₃ isC—R₂, then w₆ is C—R₁ and w₄ and w₇ are independently C—R_(a) or N; or,when w₄ is C—R₁, then w₇ is C—R₂ and w₃ is C—R_(a) or N and w₆ isC—R_(c) or N; or, when w₄ is C—R₂, then w₇ is C—R₁ and w₃ is C—R_(a) orN and w₆ is C—R_(c) or N; and, wherein any one, two or three of w₁, w₂,w₃, w₄, w₅, w₆ and w₇ may optionally be N; R₁ is C₁₋₈alkyl, amino,C₁₋₈alkyl-amino, (C₁₋₈alkyl)₂-amino, C₁₋₈alkoxy-C₁₋₈alkyl-amino,(C₁₋₈alkoxy-C₁₋₈alkyl)₂-amino, (C₁₋₈alkoxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino,amino-C₁₋₈alkyl, C₁₋₈alkyl-amino-C₁₋₈alkyl,(C₁₋₈alkyl)₂-amino-C₁₋₈alkyl, C₁₋₈alkoxy-C₁₋₈alkyl-amino-C₁₋₈alkyl,(C₁₋₈alkoxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,(C₁₋₈alkoxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl, amino-C₁₋₈alkyl-amino,(amino-C₁₋₈alkyl)₂-amino, (amino-C₁₋₈alkyl)(C₁₋₈alkyl)amino,C₁₋₈alkyl-amino-C₁₋₈alkyl-amino, (C₁₋₈alkyl-amino-C₁₋₈alkyl)₂-amino,(C₁₋₈alkyl-amino-C₁₋₈alkyl)(C₁₋₈alkyl)amino,(C₁₋₈alkyl)₂-amino-C₁₋₈alkyl-amino,[(C₁₋₈alkyl)₂-amino-C₁₋₈alkyl](C₁₋₈alkyl)amino, amino-C₁₋₈alkoxy,C₁₋₈alkyl-amino-C₁₋₈alkoxy, (C₁₋₈alkyl)₂-amino-C₁₋₈alkoxy,C₁₋₈alkoxy-C₁₋₈alkyl-amino-C₁₋₈alkoxy,C₁₋₈alkoxy-C₁₋₈alkyl-amino-C₁₋₈alkoxy,(C₁₋₈alkoxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkoxy, amino-C₂₋₈alkenyl,C₁₋₈alkyl-amino-C₂₋₈alkenyl, (C₁₋₈alkyl)₂-amino-C₂₋₈alkenyl,amino-C₂₋₈alkynyl, C₁₋₈alkyl-amino-C₂₋₈alkynyl,(C₁₋₈alkyl)₂-amino-C₂₋₈alkynyl, halo-C₁₋₈alkyl-amino,(halo-C₁₋₈alkyl)₂-amino, (halo-C₁₋₈alkyl)(C₁₋₈alkyl)amino,hydroxy-C₁₋₈alkyl, hydroxy-C₁₋₈alkoxy-C₁₋₈alkyl,hydroxy-C₁₋₈alkyl-amino, (hydroxy-C₁₋₈alkyl)₂-amino,(hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino, hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkyl,(hydroxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,(hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl,hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkoxy,(hydroxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkoxy,(hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkoxy,hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkyl-amino,(hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkyl)₂-amino,(hydroxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl-amino,(hydroxy-C₁₋₈alkyl-amino-C₁₋₈alkyl)(C₁₋₈alkyl)amino,(hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl-amino,[(hydroxy-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl](C₁₋₈alkyl)amino,[(hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl](C₁₋₈alkyl)amino,heterocyclyl, heterocyclyl-C₁₋₈alkyl, heterocyclyl-C₁₋₈alkoxy,heterocyclyl-amino, (heterocyclyl)(C₁₋₈alkyl)amino,heterocyclyl-amino-C₁₋₈alkyl, heterocyclyl-C₁₋₈alkyl-amino,(heterocyclyl-C₁₋₈alkyl)₂-amino,(heterocyclyl-C₁₋₈alkyl)(C₁₋₈alkyl)amino,heterocyclyl-C₁₋₈alkyl-amino-C₁₋₈alkyl,(heterocyclyl-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,(heterocyclyl-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl, heterocyclyl-oxy,heterocyclyl-carbonyl, heterocyclyl-carbonyl-oxy, C₃₋₁₄cycloalkyl,aryl-C₁₋₈alkyl-amino, (aryl-C₁₋₈alkyl)₂-amino,(aryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino, aryl-C₁₋₈alkyl-amino-C₁₋₈alkyl,(aryl-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,(aryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl, heteroaryl,heteroaryl-C₁₋₈alkyl, heteroaryl-C₁₋₈alkoxy, heteroaryl-amino,heteroaryl-C₁₋₈alkyl-amino, (heteroaryl-C₁₋₈alkyl)₂-amino,(heteroaryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino,heteroaryl-C₁₋₈alkyl-amino-C₁₋₈alkyl,(heteroaryl-C₁₋₈alkyl)₂-amino-C₁₋₈alkyl or(heteroaryl-C₁₋₈alkyl)(C₁₋₈alkyl)amino-C₁₋₈alkyl; wherein, each instanceof heterocyclyl, C₃₋₁₄cycloalkyl, aryl and heteroaryl is optionallysubstituted with one, two or three R₃ substituents and optionally, withone additional R₄ substituent; or, wherein, each instance ofheterocyclyl, C₃₋₁₄cycloalkyl, aryl and heteroaryl is optionallysubstituted with one, two, three or four R₃ substituents; R₂ is aryl,aryl-amino, aryl-amino-carbonyl, heterocyclyl, heteroaryl orheteroaryl-amino; wherein, each instance of aryl, heterocyclyl andheteroaryl is optionally substituted with one, two or three R₆substituents and optionally, with one additional R₇ substituent; R_(a)is, in each instance, independently selected from hydrogen, halogen,C₁₋₈alkyl or deuterium; R_(b) is hydrogen, halogen, C₁₋₈alkyl,C₁₋₈alkoxy or deuterium; R_(c) is hydrogen, halogen, C₁₋₈alkyl ordeuterium; R₃ is, in each instance, independently selected from cyano,halogen, hydroxy, oxo, C₁₋₈alkyl, halo-C₁₋₈alkyl, C₁₋₈alkyl-carbonyl,C₁₋₈alkoxy, halo-C₁₋₈alkoxy, C₁₋₈alkoxy-C₁₋₈alkyl, C₁₋₈alkoxy-carbonyl,amino, C₁₋₈alkyl-amino, (C₁₋₈alkyl)₂-amino, amino-C₁₋₈alkyl,C₁₋₈alkyl-amino-C₁₋₈alkyl, (C₁₋₈alkyl)₂-amino-C₁₋₈alkyl,amino-C₁₋₈alkyl-amino, C₁₋₈alkyl-amino-C₁₋₈alkyl-amino,(C₁₋₈alkyl-amino-C₁₋₈alkyl)₂-amino, (C₁₋₈alkyl)₂-amino-C₁₋₈alkyl-amino,[(C₁₋₈alkyl)₂-amino-C₁₋₈alkyl]₂-amino,(C₁₋₈alkyl-amino-C₁₋₈alkyl)(C₁₋₈alkyl)amino,[(C₁₋₈alkyl)₂-amino-C₁₋₈alkyl](C₁₋₈alkyl)amino,C₁₋₈alkoxy-C₁₋₈alkyl-amino, (C₁₋₈alkoxy-C₁₋₈alkyl)₂-amino,(C₁₋₈alkoxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino, C₁₋₈alkyl-carbonyl-amino,C₁₋₈alkoxy-carbonyl-amino, hydroxy-C₁₋₈alkyl,hydroxy-C₁₋₈alkoxy-C₁₋₈alkyl, hydroxy-C₁₋₈alkyl-amino,(hydroxy-C₁₋₈alkyl)₂-amino or (hydroxy-C₁₋₈alkyl)(C₁₋₈alkyl)amino; R₄ isC₃₋₁₄cycloalkyl, C₃₋₁₄cycloalkyl-C₁₋₈alkyl, C₃₋₁₄cycloalkyl-amino,aryl-C₁₋₈alkyl, aryl-C₁₋₈alkoxy-carbonyl, aryl-sulfonyloxy-C₁₋₈alkyl,heterocyclyl or heterocyclyl-C₁₋₈alkyl; wherein, each instance ofC₃₋₁₄cycloalkyl, aryl and heterocyclyl is optionally substituted withone, two or three R₅ substituents; R₅ is, in each instance,independently selected from halogen, hydroxy, cyano, nitro, C₁₋₈alkyl,halo-C₁₋₈alkyl, C₁₋₈alkoxy, halo-C₁₋₈alkoxy, amino, C₁₋₈alkyl-amino,(C₁₋₈alkyl)₂-amino or C₁₋₈alkyl-thio; R₆ is, in each instance,independently selected from halogen, hydroxy, cyano, nitro, C₁₋₈alkyl,C₂₋₈alkenyl, halo-C₁₋₈alkyl, hydroxy-C₁₋₈alkyl, C₁₋₈alkoxy,halo-C₁₋₈alkoxy, C₁₋₈alkoxy-C₁₋₈alkyl, amino, C₁₋₈alkyl-amino,(C₁₋₈alkyl)₂-amino or C₁₋₈alkyl-thio; and, R₇ is C₃₋₁₄cycloalkyl,C₃₋₁₄cycloalkyl-oxy, aryl, heterocyclyl or heteroaryl.
 29. A method ofintroducing into a human subject an artificial gene construct,comprising administering to the subject the artificial gene construct,wherein the artificial gene construct comprises: (A) a DNA sequenceencoding exons and one, two or more introns, wherein a nucleotidesequence encoding a 5′ splice site, which is upstream of a nucleotidesequence encoding a branch point and a nucleotide sequence encoding a 3′splice site, contains a nucleotide sequence encoding a recognitionelement for splicing modifier (REMS), wherein the REMS comprises thesequence GAgtrngn (SEQ ID NO:5), wherein r is A or G and n is anynucleotide; or (B) an RNA sequence comprising exons and one, two or moreintrons, wherein a 5′ splice site, which is upstream of a branch pointand a 3′ splice site, contains a REMS, wherein the REMS comprises thesequence GAgurngn (SEQ ID NO:1), wherein r is A or G and n is anynucleotide.
 30. The method of claim 24, wherein the vector is a viralvector.
 31. The method of claim 25, wherein the vector is a viralvector.
 32. The method of claim 26, wherein the vector is a viralvector.
 33. The method of claim 29, wherein the vector is a viralvector.
 34. The method of claim 30, wherein the viral vector is anadeno-associated virus, an adenovirus, a retrovirus, a lentivirus, aNewcastle disease virus, a herpes virus, an alphavirus, or a vacciniavirus.
 35. The method of claim 31, wherein the viral vector is anadeno-associated virus, an adenovirus, a retrovirus, a lentivirus, aNewcastle disease virus, a herpes virus, an alphavirus, or a vacciniavirus.
 36. The method of claim 32, wherein the viral vector is anadeno-associated virus, an adenovirus, a retrovirus, a lentivirus, aNewcastle disease virus, a herpes virus, an alphavirus, or a vacciniavirus.
 37. The method of claim 33, wherein the viral vector is anadeno-associated virus, an adenovirus, a retrovirus, a lentivirus, aNewcastle disease virus, a herpes virus, an alphavirus, or a vacciniavirus.
 38. The method of claim 24, wherein the artificial gene constructfurther comprises a promoter, a poly(A) site, a transcriptiontermination site, and a transcription binding site.
 39. The method ofclaim 25, wherein the artificial gene construct further comprises apromoter, a poly(A) site, a transcription termination site, and atranscription binding site.
 40. The method of claim 26, wherein theartificial gene construct further comprises a promoter, a poly(A) site,a transcription termination site, and a transcription binding site. 41.The method of claim 29, wherein the artificial gene construct furthercomprises a promoter, a poly(A) site, a transcription termination site,and a transcription binding site.
 42. The method of claim 24, whereinthe REMS in the DNA sequence comprises the sequence ANGAgtrngn (SEQ IDNO: 7), wherein r is A or G and n or N is any nucleotide.
 43. The methodof claim 25, wherein the REMS in the DNA sequence comprises the sequenceANGAgtrngn (SEQ ID NO: 7), wherein r is A or G and n or N is anynucleotide.
 44. The method of claim 26, wherein the REMS in the DNAsequence comprises the sequence ANGAgtrngn (SEQ ID NO: 7), wherein r isA or G and n or N is any nucleotide.
 45. The method of claim 29, whereinthe REMS in the DNA sequence comprises the sequence ANGAgtrngn (SEQ IDNO: 7), wherein r is A or G and n or N is any nucleotide.
 46. The methodof claim 24, wherein the REMS in the RNA sequence comprises the sequenceANGAgurngn (SEQ ID NO:3), wherein r is A or G and n or N is anynucleotide.
 47. The method of claim 25, wherein the REMS in the RNAsequence comprises the sequence ANGAgurngn (SEQ ID NO: 3), wherein r isA or G and n or N is any nucleotide.
 48. The method of claim 26, whereinthe REMS in the RNA sequence comprises the sequence ANGAgurngn (SEQ IDNO: 3), wherein r is A or G and n or N is any nucleotide.
 49. The methodof claim 29, wherein the REMS in the RNA sequence comprises the sequenceANGAgurngn (SEQ ID NO: 3), wherein r is A or G and n or N is anynucleotide.